Phosphatidylinositol 3-kinase inhibitors

ABSTRACT

The present disclosure provides phosphatidylinositol 3-kinase (PI3K) inhibitors of formula (I), 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts thereof, in which R 1 , R 2 , n, R 3 , R 4 , R 5  and R 6  are as defined herein. These compounds are useful for treatment of conditions mediated by one or more PI3K isoforms, such as PI3Kδ. The present disclosure further provides pharmaceutical compositions that include a compound of formula (I), or pharmaceutically acceptable salts thereof, and methods of using these compounds and compositions to treat conditions mediated by one or more PI3K isoforms, such as PI3Kδ.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/745,429, filed Dec. 21, 2012, the disclosure ofwhich is hereby incorporated by reference in its entirety.

FIELD

The present disclosure relates generally to inhibitors ofphosphatidylinositol 3-kinase (PI3K) activity and, more specifically, tonovel compounds that are selective inhibitors of PI3K delta activity.

BACKGROUND

Cell signaling via 3′-phosphorylated phosphoinositides has beenimplicated in a variety of cellular processes, e.g., malignanttransformation, growth factor signaling, inflammation, and immunity. Seegenerally Rameh et al., J. Biol. Chem., 274:8347-8350 (1999). The enzymeresponsible for generating these phosphorylated signaling products isphosphatidylinositol 3-kinase (PI 3-kinase; PI3K). PI3K originally wasidentified as an activity associated with viral oncoproteins and growthfactor receptor tyrosine kinases that phosphorylate phosphatidylinositol(PI) and its phosphorylated derivatives at the 3′-hydroxyl of theinositol ring. See Panayotou et al., Trends Cell Biol 2:358-60 (1992).

Presently, three classes of the PI 3-kinase (PI3K) enzymes aredistinguished, based on their substrate specificities. Class I PI3Ks canphosphorylate phosphatidylinositol (PI),phosphatidylinositol-4-phosphate, andphosphatidylinositol-4,5-biphosphate (PIP₂) to producephosphatidylinositol-3-phosphate (PIP),phosphatidylinositol-3,4-biphosphate, andphosphatidylinositol-3,4,5-triphosphate, respectively. Class II PI3Ksphosphorylate PI and phosphatidylinositol-4-phosphate, whereas Class IIIPI3Ks can only phosphorylate PI.

The initial purification and molecular cloning of PI 3-kinase revealedthat it was a heterodimer consisting of p85 and p110 subunits. See Otsuet al., Cell, 65:91-104 (1991); Hiles et al., Cell, 70:419-29 (1992).Since then, four distinct Class I PI3Ks have been identified, designatedPI3K α, β, δ, and γ, each consisting of a distinct 110 kDa catalyticsubunit and a regulatory subunit. More specifically, three of thecatalytic subunits, i.e., p110α, p110β, and p110δ, each interact withthe same regulatory subunit, i.e., p85, whereas p110γ interacts with adistinct p101 regulatory subunit. As described below, the patterns ofexpression of each of these PI3Ks in human cells and tissues also aredistinct.

Identification of the p110δ isoform of PI 3-kinase is described inChantry et al., J. Biol. Chem., 272:19236-41 (1997). It was observedthat the human p110δ isoform is expressed in a tissue-restrictedfashion. It is expressed at high levels in lymphocytes and lymphoidtissues, suggesting that the protein might play a role in PI3-kinase-mediated signaling in the immune system. Details concerning thep110δ isoform also can be found in U.S. Pat. Nos. 5,858,753; 5,822,910;and 5,985,589, each of which is incorporated herein by reference. Seealso Vanhaesebroeck et al., Proc. Natl. Acad. Sci. USA, 94:4330-5(1997); and WO 97/46688.

A need remains, however, for additional therapeutic agents useful totreat proliferative disorders or diseases that are mediated by PI3K. Thepresent invention provides novel compounds that are inhibitors of PI3Kisoforms.

SUMMARY

Compounds and pharmaceutically acceptable salts thereof useful forinhibiting PI3K isoforms, such as PI3Kδ, are described herein.Compositions, including pharmaceutical compositions, and kits thatinclude the compounds are also provided, as are methods of using andmaking the compounds. The compounds provided herein may find use intreating diseases, disorders, or conditions that are mediated by PI3Kisoforms, such as PI3Kδ.

In one aspect, provided is a compound of Formula (I):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein:

R¹ is unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, or unsubstituted or substituted alkyl;

n is 0, 1, 2, or 3;

each R² is independently halo or unsubstituted or substituted alkyl;

R³ is unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, or unsubstituted orsubstituted heterocycloalkyl;

R⁴ is hydrogen, alkyl, or NH₂;

R⁵ is alkyl; and

R⁶ is hydrogen, or R⁵ together with the carbon to which it is attachedand R⁶ together with the nitrogen to which it is attached are takentogether to form a four-, five- or six-membered heterocycle.

In another aspect, provided herein is also a compound of formula (IA):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein:

R¹ is unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, or unsubstituted or substituted alkyl;

n is 0, 1, 2, or 3;

each R² is independently halo or unsubstituted or substituted alkyl;

R³ is unsubstituted or substituted aryl; and

R⁴ is hydrogen or NH₂.

In yet another aspect, provided herein is also a compound of formula(TB):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein:

R¹ is unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, or unsubstituted or substituted alkyl;

n is 0, 1, 2, or 3;

each R² is independently halo or unsubstituted or substituted alkyl;

R⁴ is hydrogen or NH₂;

m is 0, 1 or 2; and

each R⁷ is independently halo, —C(O)NR^(3a)R^(3b) and—S(O)₂NR^(3a)R^(3b),

-   -   wherein R^(3a) and R^(3b) are independently hydrogen or C₁₋₆        alkyl.

In yet another aspect, provided herein is also a compound of formula(IC):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein:

R¹ is unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, or unsubstituted or substituted alkyl;

R^(2a) and R^(2b) are independently hydrogen, halo or unsubstituted orsubstituted alkyl;

R⁴ is hydrogen or NH₂; and

R^(7a) and R^(7b) are independently hydrogen, halo, —C(O)NR^(3a)R^(3b)and —S(O)₂NR^(3a)R^(3b),

-   -   wherein R^(3a) and R^(3b) are independently hydrogen or C₁₋₆        alkyl.

Provided is also a compound of formula (II):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein:

R¹ is unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, or unsubstituted or substituted alkyl;

n is 0, 1, 2, or 3;

each R² is independently halo, OH, CN, unsubstituted or substitutedalkyl, haloalkyl, or SO₂R^(2a), wherein R^(2a) is alkyl;

R³ is unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, or unsubstituted orsubstituted heterocycloalkyl;

R⁴ is hydrogen, alkyl, or NH₂;

R⁵ is alkyl or alkyl substituted with OH or OR^(5a), wherein R^(5a) isalkyl; and

R⁶ is hydrogen, or R⁵ together with the carbon to which it is attachedand R⁶ together with the nitrogen to which it is attached are takentogether to form a four-, five- or six-membered heterocycle.

In yet another aspect, provided is a compound selected from Table 1, ora pharmaceutically acceptable salt, prodrug, or solvate thereof. In yetanother aspect, provided is a compound selected from Table 1a, or apharmaceutically acceptable salt, prodrug, or solvate thereof.

Also provided is a pharmaceutical composition that includes a compoundof formula (I), (IA), (IB), (IC), or (II), or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof, together with at least onepharmaceutically acceptable vehicle. Examples of pharmaceuticallyacceptable vehicle may be selected from carriers, adjuvants, andexcipients.

Also provided is a method of treating a subject, who has or is suspectedof having a disease or condition responsive or believed to be responsiveto the inhibition of PI3Kδ activity by administering to the subject acompound of formula (I), (IA), (IB), (IC), or (II), or apharmaceutically acceptable salt, prodrug, or solvate thereof. In someembodiments, the subject is a human.

Also provided is a kit that includes a compound of formula (I), (IA),(IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, orsolvate thereof; and a label and/or instructions for use of the compoundin the treatment of a disease or condition mediated by PI3Kδ activity.

Also provided are articles of manufacture that include a compound offormula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptablesalt, prodrug, or solvate thereof; and a container. In one embodiment,the container may be a vial, jar, ampoule, preloaded syringe, or anintravenous bag.

DETAILED DESCRIPTION

The following description sets forth exemplary methods, parameters andthe like. It should be recognized, however, that such description is notintended as a limitation on the scope of the present disclosure but isinstead provided as a description of exemplary embodiments.

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

“Alkyl” refers to a monoradical unbranched or branched saturatedhydrocarbon chain. In some embodiments, alkyl as used herein, such as incompounds of formula (I), (IA), (IB), (IC), or (II), has 1 to 20 carbonatoms (i.e., C₁₋₂₀ alkyl), 1 to 8 carbon atoms (i.e., C₁₋₈ alkyl), 1 to6 carbon atoms (i.e., C₁₋₆ alkyl), or 1 to 4 carbon atoms (i.e., C₁₋₄alkyl). Examples of alkyl groups include methyl, ethyl, propyl,isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl,neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkylresidue having a specific number of carbons is named, all geometricisomers having that number of carbons may be encompassed; thus, forexample, “butyl” can include n-butyl, sec-butyl, isobutyl and t-butyl;“propyl” can include n-propyl and isopropyl. In some embodiments, “loweralkyl” refers to alkyl groups having 1 to 6 carbons (i.e., C₁₋₆ alkyl).

“Cycloalkyl” refers to a cyclic alkyl group. In some embodiments,cycloalkyl as used herein, such as in compounds of formula (I), (IA),(IB), (IC), or (II), has from 3 to 20 ring carbon atoms (i.e., C₃₋₂₀cycloalkyl), or 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), or 3to 8 ring carbon atoms (i.e., C₃₋₈ cycloalkyl). Examples of cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

“Heterocycloalkyl” refers to a cyclic alkyl group, with one or more ringheteroatoms independently selected from nitrogen, oxygen and sulfur. Insome embodiments, the heterocycloalkyl as used herein, such as incompounds of formula (I), (IA), (IB), (IC), or (II), has 2 to 20 ringcarbon atoms (i.e., C₂₋₂₀ heterocycloalkyl), 2 to 12 ring carbon atoms(i.e., C₂₋₁₂ heterocycloalkyl), or 2 to 8 ring carbon atoms (i.e., C₂₋₈heterocycloalkyl); and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms,1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatomindependently selected from nitrogen, sulfur or oxygen. In one example,a heterocycloalkyl has 2 to 8 ring carbon atoms, with 1 to 3 ringheteroatoms independently selected from nitrogen, oxygen and sulfur.Examples of heterocycloalkyl groups may include pyrrolidinyl,piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, andmorpholinyl. The heterocycloalkyl may have one or more rings. Forexample, the heterocycloalkyl may be monocyclic or bicyclic.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g., phenyl), multiple rings (e.g., biphenyl), or multiple fused rings(e.g., naphthyl, fluorenyl, and anthryl). In certain embodiments, arylas used herein, such as in compounds of formula (I), (IA), (IB), (IC),or (II), has 6 to 20 ring carbon atoms (i.e., C₆₋₂₀ aryl), or 6 to 12carbon ring atoms (i.e., C₆₋₁₂ aryl). Aryl, however, does not encompassor overlap in any way with heteroaryl, separately defined below. Incertain embodiments, if one or more aryl groups are fused with aheteroaryl ring, the resulting ring system is heteroaryl.

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings, or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen, and sulfur, in someembodiments, heteroaryl is an aromatic, monocyclic or bicyclic ringcontaining one or more heteroatoms independently selected from nitrogen,oxygen and sulfur with the remaining ring atoms being carbon. In certainembodiments, heteroaryl as used herein, such as in compounds of formula(I), (IA), (IB), (IC), or (II), has 3 to 20 ring carbon atoms (i.e.,C₃₋₂₀ heteroaryl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ heteroaryl),or 3 to 8 carbon ring atoms (i.e., C₃₋₈ heteroaryl) and 1 to 5heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ringheteroatoms, or 1 ring heteroatom independently selected from nitrogen,oxygen, and sulfur. In one example, a heteroaryl has 3 to 8 ring carbonatoms, with 1 to 3 ring heteroatoms independently selected fromnitrogen, oxygen and sulfur. Examples of heteroaryl groups include, butare not limited to, pyridyl, pyridazinyl, pyrimidinyl, benzothiazolyl,and pyrazolyl. In one embodiment, heteroaryl is selected from 2-pyridyl,3-pyridyl, 3-pyridazinyl, 2-pyrazinyl, benzo[d]thiazol-6-yl, and4-pyrazolyl Heteroaryl does not encompass or overlap with aryl asdefined above.

The term “substituted”, as used herein, means that any one or morehydrogen atoms on the designated atom or group is replaced with a moietyother than hydrogen, provided that the designated atom's normal valenceis not exceeded.

“Substituted alkyl” refers to an alkyl group having one or moresubstituents including, for example, hydroxyl, haloalkyl, alkoxy,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, cyano, halo, andcarboxyl. In some embodiments, a substituted alkyl may have 1 to 5substituents, 1 to 3 substituents, 1 to 2 substituents, or 1substituent.

“Substituted cycloalkyl” refers to a cycloalkyl group having one or moresubstituents including, for example, alkyl, haloalkyl, heterocycloalkyl,aryl, heteroaryl, alkoxy, amino, cyano, halo, carboxyl, and hydroxyl. Insome embodiments, a substituted cycloalkyl may have 1 to 5 substituents,1 to 3 substituents, 1 to 2 substituents, or 1 substituent.

“Substituted heterocycloalkyl” refers to a heterocycloalkyl group havingone or more substituents including, for example, alkyl, haloalkyl,cycloalkyl, aryl, heteroaryl, alkoxy, amino, cyano, halo, carboxyl, andhydroxyl. In some embodiments, a substituted heterocycloalkyl may have 1to 5 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1substituent. In certain embodiments, a substituted heterocycloalkyl maycontain 1, 2 or 3 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

“Substituted aryl” refers to an aryl group having one or moresubstituents including, for example, halo, OR, —C(O)NR₂, —SO₂NR₂, alkyl,haloalkyl, heterocycloalkyl, heteroaryl, alkoxy, amino, cyano, andcarboxyl, where each R is independently selected from hydrogen, alkyl,and haloalkyl. In some embodiments, a substituted aryl may have 1 to 5substituents, 1 to 3 substituents, 1 to 2 substituents, or 1substituent.

“Substituted heteroaryl” refers to a heteroaryl group having one or moresubstituents including, for example, alkyl, haloalkyl, halo, NH₂, OR,—C(O)OR, heterocycloalkyl, aryl, and cyano, where each R isindependently selected from hydrogen, alkyl, and haloalkyl. In someembodiments, a substituted heteroaryl may have 1 to 5 substituents, 1 to3 substituents, 1 to 2 substituents, or 1 substituent. In certainembodiments, a substituted heteroaryl may contain 1, 2 or 3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

The term “halogen” or “halo” includes fluoro, chloro, bromo, and iodo,and the term “halogen” includes fluorine, chlorine, bromine, and iodine.“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms are replaced by a halogen. Forexample, where a residue is substituted with more than one halogen, itmay be referred to by using a prefix corresponding to the number ofhalogen moieties attached. For example, dihaloaryl, dihaloalkyl, andtrihaloaryl refer to aryl and alkyl substituted with two (“di”) or three(“tri”) halo groups, which may be, but are not necessarily, the samehalogen; thus, for example, 3,5-difluorophenyl, 3-chloro-5-fluorophenyl,4-chloro-3-fluorophenyl, and 3,5-difluoro-4-chlorophenyl is within thescope of dihaloaryl. Other examples of a haloalkyl group includedifluoromethyl (—CHF₂) and trifluoromethyl (—CF₃). It should beunderstood that trifluoromethyl (—CF₃) may also be referred to asperfluoromethyl.

PI3K Inhibitor Compounds

Provided herein are compounds that function as PI3Kδ inhibitors. In oneaspect, provided is a compound of formula (I):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein:

R¹ is unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, or unsubstituted or substituted alkyl;

n is 0, 1, 2, or 3;

each R² is independently halo or unsubstituted or substituted alkyl;

R³ is unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, or unsubstituted orsubstituted heterocycloalkyl;

R⁴ is hydrogen, alkyl, or —NH₂;

R⁵ is alkyl; and

R⁶ is hydrogen, or R⁵ together with the carbon to which it is attachedand R⁶ together with the nitrogen to which it is attached are takentogether to form a four-, five- or six-membered heterocycle.

In some embodiments of formula (I), R¹ is:

unsubstituted aryl;

unsubstituted heteroaryl;

unsubstituted cycloalkyl;

aryl, heteroaryl, or cycloalkyl substituted with 1 or 2 substituentsindependently selected from the group consisting of halo, —OR^(1a),—C(O)OR^(1a), —C(O)R^(1a), NH₂, alkyl, and haloalkyl, wherein R^(1a) isalkyl or haloalkyl;

unsubstituted alkyl; or

alkyl substituted with OH.

In certain embodiments of formula (I), R¹ is:

unsubstituted C₆₋₁₂ aryl;

C₆₋₁₂ aryl substituted with 1 or 2 substituents independently selectedfrom the group consisting of halo and —OR^(1b), wherein R^(1b) is C₁₋₆alkyl or C₁₋₆ haloalkyl;

unsubstituted C₃₋₁₂ heteroaryl with 1 or 2 heteroatoms independentlyselected from the group consisting of nitrogen and sulfur;

C₃₋₁₂ heteroaryl with 1 or 2 heteroatoms independently selected from thegroup consisting of nitrogen and sulfur, and substituted with 1 or 2substituents independently selected from the group consisting of halo,—OR^(1c), C(O)OR^(1c), —C(O)R^(1c), NH₂, and C₁₋₆ haloalkyl, whereinR^(1c) is C₁₋₆ alkyl or C₁₋₆ haloalkyl;

unsubstituted C₃₋₁₂ cycloalkyl;

unsubstituted C₁₋₆ alkyl; or

C₁₋₆ alkyl substituted with OH.

In one embodiment of formula (I), R¹ is substituted C₁₋₆ alkyl. Forexample, the substituted C₁₋₆ alkyl is -hydroxyethyl orhydroxy-isopropyl.

In certain embodiments of formula, R¹ is:

unsubstituted phenyl;

phenyl substituted with 1 or 2 substituents independently selected fromthe group consisting of fluoro and —OR^(1b), wherein R^(1b) is methyl orperfluoromethyl;

unsubstituted pyridyl;

pyridyl substituted with 1 or 2 substituents independently selected fromthe group consisting of fluoro, —C(O)OR^(1c), —C(O)R^(1c), NH₂,perfluoromethyl, wherein R^(1c) is methyl or perfluoromethyl;

unsubstituted pyridazinyl;

unsubstituted pyrazinyl;

unsubstituted pyrimidinyl;

pyrimidinyl substituted with NH₂;

unsubstituted pyrazolyl;

unsubstituted benzothiazolyl; or

benzothiazolyl substituted with NH₂.

In certain embodiments of formula (I), R¹ is:

In one embodiment of formula (I), R¹ is:

It is intended and understood that each and every variation of R¹ may becombined with each and every variation of n and R², R³, R⁴, R⁵ and R⁶ asdescribed for formula (I), as if each and every combination isindividually described.

In one embodiment of formula (I), n is 0. In other embodiments, n is 1,2 or 3. In certain embodiments, n is 1 or 2. In one embodiment, n is 1.The R² moiety may be located on any position of the quinazolinone ring,as depicted below.

In another embodiment, n is 2. In embodiments where n is 2, both R² maybe the same or different. Two R² moieties may be located of any twopositions of the quinazolinone ring as depicted below. For example, twoR² moieties may be in para-, meta- or ortho-positions to each other.

In yet another embodiment, n is 3. In embodiments where n is 3, all R²may be the same or different, or two R² may be the same and differentfrom the third R². Three R² moieties may be located on any threepositions of the quinazolinone ring as depicted below. For example, thefirst R² may be ortho to the second R², and the first R² may be para tothe third R².

In some embodiments, each R² is independently halo or unsubstitutedalkyl, alkyl substituted with cyano or haloalkyl. In certainembodiments, R² is independently fluoro, chloro, methyl, or halomethyl.In one embodiment, n is 0. In another embodiment, n is 1, wherein R² isfluoro or chloro. In yet another embodiment, n is 2, wherein each R² isindependently fluoro or chloro.

It is intended and understood that each and every variation of n and R²may be combined with each and every variation of R¹, R³, R⁴, R⁵ and R⁶as described for formula (I), as if each and every combination isindividually described.

In some embodiments, R³ is:

unsubstituted C₆₋₁₂ aryl; or

C₆₋₁₂ aryl substituted with 1 or 2 substituents independently selectedfrom the group consisting of halo, alkyl, haloalkyl, cyano,—C(O)NR^(3a)R^(3b) and —SO₂NR^(3a)R^(3b), wherein R^(3a) and R^(3b) areindependently hydrogen or C₁₋₆ alkyl.

In certain embodiments, R³ is:

unsubstituted phenyl; or

phenyl substituted with 1 or 2 substituents independently selected fromthe group consisting of fluoro, chloro, cyano, halomethyl,—C(O)NR^(3a)R^(3b) and —S(O)₂NR^(3a)R^(3b), wherein R^(3a) and R^(3b)are independently hydrogen, methyl or ethyl.

In certain embodiments, R³ is:

In one embodiment, R³ is:

It is intended and understood that each and every variation of R³ may becombined with each and every variation of R¹, n, R², R⁴, R⁵ and R⁶ asdescribed for formula (I), as if each and every combination isindividually described.

In some embodiments, R⁴ is R⁴ is hydrogen, C₁₋₆ alkyl, or NH₂. In oneembodiment, R is hydrogen. In another embodiment, R⁴ is methyl. In yetanother embodiment, R⁴ is NH₂.

It is intended and understood that each and every variation of R⁴ may becombined with each and every variation of R¹, n, R², R³, R⁵ and R⁶ asdescribed for formula (I), as if each and every combination isindividually described.

In some embodiments, R⁵ is C₁₋₆ alkyl. In one embodiment, R⁵ is methyl.In one embodiment, R⁶ is hydrogen. In other embodiments, R⁵ togetherwith the carbon to which it is attached and R⁶ together with thenitrogen to which it is attached are taken together to form a five- orsix-membered heterocycloalkyl.

It is intended and understood that each and every variation of R⁵ may becombined with each and every variation of R¹, n, R², R³, R⁴ and R⁶ asdescribed for formula (I), as if each and every combination isindividually described.

In some embodiments, the compound of formula (I) is the (S)-enantiomer.In other embodiments of formula (II), the compound of formula (II) isthe (R)-enantiomer. In certain embodiments, the compound has thestructure of formula (I′):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein R¹, R², n, R³, R⁴, R⁵ and R⁶ are as defined above for compoundsof formula (I).

In some embodiments, the compound of formula (I) is a compound offormula (IA):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein R¹, R², n, R³, and R⁴ are as defined above for compounds offormula (I). In some embodiments, the compound of formula (IA) is the(S)-enantiomer.

In certain embodiments of formula (IA),

R¹ is unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, or unsubstituted or substituted alkyl;

n is 0, 1, 2, or 3;

each R² is independently halo or alkyl;

R³ is unsubstituted or substituted aryl; and

R⁴ is hydrogen or NH₂.

In other embodiments, the compound of formula (I) is a compound offormula (IB):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein:

R¹, R², n, and R⁴ are as defined above for compounds of formula (I);

m is 0, 1 or 2; and

each R⁷ is independently halo, —C(O)NR^(3a)R^(3b) and—S(O)₂NR^(3a)R^(3b),

-   -   wherein R^(3a) and R^(3b) are independently hydrogen or C₁₋₆        alkyl.

In certain embodiments of formula (IB),

R¹ is unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, or unsubstituted or substituted alkyl;

n is 0, 1, 2, or 3;

each R² is independently halo or unsubstituted or substituted alkyl;

R⁴ is hydrogen or NH₂;

m is 0, 1 or 2; and

each R⁷ is independently halo, —C(O)NR^(3a)R^(3b) and—S(O)₂NR^(3a)R^(3b),

-   -   wherein R^(3a) and R^(3b) are independently hydrogen or C₁₋₆        alkyl.

In some embodiments, the compound of formula (IB) is the (S)-enantiomer.In some embodiments, each R⁷ is independently fluoro, —C(O)NH₂,—S(O)₂NR^(3a)R^(3b), wherein R^(3a) and R^(3b) are independentlyhydrogen, methyl, or ethyl. In one embodiment, m is 0. In anotherembodiment, m is 1, and R⁷ is —C(O)NH₂, —S(O)₂NR^(3a)R^(3b), whereinR^(3a) and R^(3b) are independently hydrogen, methyl, or ethyl. In yetanother embodiment, m is 2, and each R⁷ is fluoro.

In yet other embodiments, the compound of formula (I) is a compound offormula (IC):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein:

R¹ and R⁴ are as defined above for compounds of formula (I);

R^(2a) and R^(2b) are independently hydrogen, halo or unsubstituted orsubstituted alkyl; and

R^(7a) and R^(7b) are independently hydrogen, halo, —C(O)NR^(3a)R^(3b)and —S(O)₂NR^(3a)R^(3b),

-   -   wherein R^(3a) and R^(3b) are independently hydrogen or C₁₋₆        alkyl.

In certain embodiments of formula (IC),

R¹ is unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, or unsubstituted or substituted alkyl;

R^(2a) and R^(2b) are independently hydrogen, halo or unsubstituted orsubstituted alkyl;

R⁴ is hydrogen, alkyl, or NH₂; and

R^(7a) and R^(7b) are independently hydrogen, halo, —C(O)NR^(3a)R^(3b)and —S(O)₂NR^(3a)R^(3b),

-   -   wherein R^(3a) and R^(3b) are independently hydrogen or C₁₋₆        alkyl.

In some embodiments, the compound of formula (IC) is the (S)-enantiomer.In some embodiments, R^(2a) and R^(2b) are independently halo orunsubstituted alkyl, alkyl substituted with cyano or haloalkyl. Incertain embodiments, R^(2a) and R^(2b) are independently hydrogen,fluoro, chloro, or C₁₋₆-alkyl. In one embodiment, R^(2a) and R^(2b) areboth fluoro or are both chloro. In another embodiment, one of R^(2a) andR^(2b) is hydrogen, and the other is fluoro or chloro. In yet anotherembodiment, one of R^(2a) and R^(2b) is fluoro, and the other is chloro.In yet another embodiment, one of R^(2a) and R^(2b) is hydrogen, and theother is methyl.

In some embodiments, R^(7a) and R^(7b) are independently hydrogen,fluoro, chloro, —C(O)NR^(3a)R^(3b) and —S(O)₂NR^(3a)R^(3b), and R^(3a)and R^(3b) are independently hydrogen, methyl or ethyl. In oneembodiment, R^(7a) and R^(7b) are both hydrogen or are both fluoro. Inanother embodiment, one of R^(7a) and R^(7b) is hydrogen, and the otheris —C(O)NH₂, —S(O)₂NR^(3a)R^(3b), wherein R^(3a) and R^(3b) areindependently hydrogen, methyl, or ethyl.

It should be understood that the embodiments and structures as describedherein with respect to formula (I) are suitable for compounds of anyformulae detailed herein, including (IA), (IB), and (IC) whereapplicable.

In another aspect, provided is a compound having the structure offormula (II):

or a pharmaceutically acceptable salt, prodrug, or solvate thereof,wherein:

R¹ is unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, or unsubstituted or substituted alkyl;

n is 0, 1, 2, or 3;

each R² is independently halo, OH, CN, unsubstituted or substitutedalkyl, haloalkyl, or SO₂R^(2a), wherein R^(2a) is alkyl;

R³ is unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, or unsubstituted orsubstituted heterocycloalkyl;

R⁴ is hydrogen, alkyl, or NH₂;

R⁵ is alkyl or alkyl substituted with OH or OR^(5a), wherein R^(5a) isalkyl; and

R⁶ is hydrogen, or R⁵ together with the carbon to which it is attachedand R⁶ together with the nitrogen to which it is attached are takentogether to form a four-, five- or six-membered heterocycle.

In some embodiments of formula (II), R¹ is:

unsubstituted aryl;

unsubstituted heteroaryl;

unsubstituted cycloalkyl;

aryl, heteroaryl, or cycloalkyl substituted with 1 or 2 substituentsindependently selected from the group consisting of halo, —OR^(1a),—C(O)OR^(1a), —C(O)R^(1a), NH₂, alkyl, haloalkyl, and C₁₋₆ alkylsubstituted with OH or NH₂, wherein R^(1a) is H, alkyl, haloalkyl, NH₂,or —O(C₁₋₆ alkyl);

unsubstituted alkyl; or

alkyl substituted with OH.

In some embodiments of formula (II), R¹ is aryl, heteroaryl, orcycloalkyl substituted with C₁₋₆ alkyl substituted with OH or NH₂,wherein R^(1a) is H, alkyl, haloalkyl, NH₂, or —O(C₁₋₆ alkyl).

In other embodiments of formula (II), R¹ is:

unsubstituted C₆₋₁₂ aryl;

C₆₋₁₂ aryl substituted with 1 or 2 substituents independently selectedfrom the group consisting of halo, —OR^(1b), —C(O)R^(1b) and C₁₋₆ alkylsubstituted with OH, wherein R^(1b) is C₁₋₆ alkyl or C₁₋₆ haloalkyl;

unsubstituted C₃₋₁₂ heteroaryl with 1 or 2 heteroatoms independentlyselected from the group consisting of nitrogen, oxygen and sulfur;

C₃₋₁₂ heteroaryl with 1 or 2 heteroatoms independently selected from thegroup consisting of nitrogen, oxygen and sulfur, and substituted with 1or 2 substituents independently selected from the group consisting ofhalo, —OR^(1c), —C(O)OR^(1c), —C(O)R^(1c), NH₂, C₁₋₆ haloalkyl, C₁₋₆alkyl, and C₁₋₆ alkyl substituted with OH or NH₂, wherein R^(1c) is H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, NH₂, or —O(C₁₋₆ alkyl);

unsubstituted C₃₋₁₂ cycloalkyl;

unsubstituted C₁₋₆ alkyl; or

C₁₋₆ alkyl substituted with OH.

In certain embodiments of formula (II), R is:

unsubstituted cyclopentyl;

unsubstituted cyclohexyl;

unsubstituted phenyl;

phenyl substituted with 1 or 2 substituents independently selected fromthe group consisting of fluoro, —OR^(1b), —C(O)R^(1b), and CH₂OH,wherein R^(1b) is methyl or perfluoromethyl;

unsubstituted pyridyl;

pyridyl substituted with 1 or 2 substituents independently selected fromthe group consisting of fluoro, —OR^(1c), —C(O)OR^(1c), —C(O)R^(1c),NH₂, methyl, ethyl, perfluoromethyl, CHF₂, CH₂OH, CH(CH₃)OH, and CH₂NH₂,wherein R^(1c) is H, methyl, perfluoromethyl, NH₂, or —OCH(CH₃)₂;

unsubstituted pyridazinyl;

unsubstituted pyrazinyl;

unsubstituted pyrimidinyl;

pyrimidinyl substituted with NH₂;

unsubstituted pyrazolyl;

unsubstituted benzothiazolyl; or

benzothiazolyl substituted with NH₂.

In one embodiment of formula (II), R¹ is:

It is intended and understood that each and every variation of R¹ may becombined with each and every variation of n, R², R³, R⁴, R⁵ and R⁶ asdescribed for formula (II), as if each and every combination isindividually described.

In one embodiment of formula (iiII), n is 0. In other embodiments, n is1, 2 or 3. In certain embodiments, n is 1 or 2. In one embodiment, nis 1. The R² moiety in formula (II) may be located on any position ofthe quinazolinone ring, as depicted above for formula (I).

In some embodiments of formula (II), each R² is independently selectedfrom the group consisting of halo, OH, CN, unsubstituted alkyl, alkylsubstituted with cyano or haloalkyl, haloalkyl, and SO₂R^(2a), whereinR^(2a) is alkyl. In certain embodiments, each R² is independentlyfluoro, chloro, OH, CN, methyl, CF₃, CHF₂, or SO₂CH₃. In one embodiment,each R² is independently OH, CN, haloalkyl, or SO₂R^(2a), wherein R^(2a)is alkyl.

It is intended and understood that each and every variation of R² may becombined with each and every variation of n, R¹, R³, R⁴, R⁵ and R⁶ asdescribed for formula (II), as if each and every combination isindividually described.

In some embodiments of formula (II), R³ is:

unsubstituted C₆₋₁₂ aryl;

C₆₋₁₂ aryl substituted with 1 or 2 substituents independently selectedfrom the group consisting of halo, alkyl, haloalkyl, aryl, cyano,—OR^(3a), —C(O)NR^(3a)R^(3b), —SO₂R^(3a), —SO₂NR^(3a)R^(3b), alkylsubstituted with NR^(3a)R^(3b), wherein R^(3a) and R^(3b) areindependently hydrogen, C₁₋₆ alkyl, or —SO₂R^(3c), wherein R^(3c) isalkyl;

unsubstituted C₃₋₁₂ heteroaryl with 1 or 2 heteroatoms independentlyselected from the group consisting of nitrogen, oxygen and sulfur;

unsubstituted C₃₋₁₂ heterocycloalkyl with 1 or 2 heteroatomsindependently selected from the group consisting of nitrogen, oxygen andsulfur; or

C₃₋₁₂ heterocycloalkyl with 1 or 2 heteroatoms independently selectedfrom the group consisting of nitrogen, oxygen and sulfur, andsubstituted with 1 or 2 alkyl substituents.

In certain embodiments of formula (II), R³ is:

unsubstituted phenyl; or

phenyl substituted with 1 or 2 substituents independently selected fromthe group consisting of fluoro, chloro, methyl, ethyl, propyl, butyl,phenyl, cyano, halomethyl, —OR^(3a), —C(O)NR^(3a)R^(3b), —SO₂R^(3a),—S(O)₂NR^(3a)R^(3b), methyl substituted with NR^(3a)R^(3b), whereinR^(3a) and R^(3b) are independently hydrogen, methyl, ethyl, propyl,butyl, or —SO₂R^(3c), wherein R^(3c) is methyl, ethyl, propyl, butyl.

In one embodiment of formula (II), R³ is:

It is intended and understood that each and every variation of R³ may becombined with each and every variation of R¹, n, R², R⁴, R⁵ and R⁶ asdescribed for formula (II), as if each and every combination isindividually described.

In some embodiments of formula (II), R⁴ is hydrogen, C₁₋₆ alkyl, or NH₂.In one embodiment, R⁴ is hydrogen. In another embodiment, R⁴ is methyl.In yet another embodiment, R⁴ is NH₂.

It is intended and understood that each and every variation of R⁴ may becombined with each and every variation of R¹, n, R², R³, R⁵ and R⁶ asdescribed for formula (II), as if each and every combination isindividually described.

In some embodiments of formula (II), R⁵ is C₁₋₆ alkyl. In oneembodiment, R⁵ is methyl. In one embodiment, R⁶ is hydrogen. In otherembodiments, R⁵ together with the carbon to which it is attached and R⁶together with the nitrogen to which it is attached are taken together toform a five- or six-membered heterocycloalkyl. In some embodiments offormula (II), R⁵ is alkyl substituted with OH or OR^(5a), wherein R^(5a)is alkyl.

It is intended and understood that each and every variation of R⁵ may becombined with each and every variation of R¹, n, R², R³, R⁴ and R⁶ asdescribed for formula (II), as if each and every combination isindividually described.

In some embodiments of formula (II), the compound of formula (II) is the(S)-enantiomer. In other embodiments of formula (II), the compound offormula (II) is the (R)-enantiomer.

For compounds of the invention, including the compounds of formula (I),(IA), (IB), (IC), or (II), or a pharmaceutically acceptable saltthereof, bearing one or more chiral centers, each unique stereoisomerhas a compound number bearing a suffix “a”, “b”, etc. As an example,Compound 1 bearing one chiral center can be resolved into its individualenantiomers 1a and 1b.

In any one of the foregoing embodiments, the compound of formula (I),(IA), (IB), (IC), or (II), or a pharmaceutically acceptable saltthereof, is the (S)-enantiomer. In other embodiments. In someembodiments of formula (II), the compound of formula (II) is the(R)-enantiomer.

A composition containing a mixture of enantiomers of the compound offormula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptablesalt thereof, is also provided herein. In some embodiments, thecomposition contains the (S)-enantiomer of the compound and issubstantially free of its corresponding (R)-enantiomer. In certainembodiments, a composition substantially free of the (R)-enantiomer hasless than or about 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 1%, 0.05%, or0.01% of the (R)-enantiomer. In other embodiments, the compositioncontaining the (S)-enantiomer of a compound of formula (I), (IA), (IB),(IC), or (II), or a pharmaceutically acceptable salt thereof,predominates over its corresponding (R)-enantiomer by a molar ratio ofat least or about 9:1, at least or about 19:1, at least or about 40:1,at least or about 80:1, at least or about 160:1, or at least or about320:1.

The composition containing a compound of formula (I), (IA), (IB), (IC),or (II), or a pharmaceutically acceptable salt thereof, may also containthe compound in enantiomeric excess (e.e.). For instance, a compoundwith 95% (S)-isomer and 5% (R)-isomer will have an e.e. of 90%. In someembodiments, the compound has an e.e. of at least or about 60%, 75%,80%, 85%, 90%, 95%, 98% or 99%. In some of the foregoing embodiments,the compound is enantiomerically-enriched in the (S)-isomer of compoundof formula (I), (IA), (IB), (IC), or (II).

Provided is also a composition comprising a mixture of the(S)-enantiomer and the (R)-enantiomer of a compound of formula (I),(IA), (IB), (IC), or (II), or a pharmaceutically acceptable saltthereof. In one embodiment, the mixture is a racemic mixture. In otherembodiments, the composition comprises the (S)-enantiomer of a compoundof formula (I), (IA), (IB), (IC), or (II), or a pharmaceuticallyacceptable salt thereof, wherein the (S)-enantiomer of the compound ispresent in excess of over the corresponding the (R)-enantiomer of thecompound, or a pharmaceutically acceptable salt thereof.

In any one of the foregoing embodiments, the compound of formula (I),(IA), (IB), (IC), or (II), or a pharmaceutically acceptable saltthereof, is an atropisomer. A composition containing a mixture ofatropisomers of the compound of formula (I), (IA), (IB), (IC), or (II),or a pharmaceutically acceptable salt thereof, is also provided herein.“Atropisomers” refers to conformational stereoisomers which occur whenrotation about a single bond in the molecule is prevented, or greatlyslowed, as a result of steric interactions with other parts of themolecule and the substituents at both ends of the single bond areasymmetrical, i.e., they do not require a stereocenter. Where therotational barrier about the single bond is high enough, andinterconversion between conformations is slow enough, separation andisolation of the isomeric species may be permitted. Atropisomers areenantiomers without a single asymmetric atom. As an example, Compound 81can be resolved into its individual atropisomers as depicted below.

Representative compounds of the invention are listed in Table 1 andTable 1a below in its non-isomeric form. The compounds in Table 1 andTable 1a are named using ChemBioDraw Ultra 12.0 and it should beunderstood that other names may be used to identify compounds of thesame structure. Other compounds or radicals may be named with commonnames, or systematic or non-systematic names. The compounds may also benamed using other nomenclature systems and symbols that are commonlyrecognized in the art of chemistry including, for example, ChemicalAbstract Service (CAS) and International Union of Pure and AppliedChemistry (IUPAC), The naming and numbering of the compounds of thepresent disclosure is illustrated with representative compounds offormula (I), (IA), (IB), (IC), or (II) shown in Table 1 and Table 1abelow. The compounds provided in Table 1 and Table 1a may be a singleenantiomer (e.g., (S)-enantiomer, (R)-enantiomer), or the compounds maybe present in a composition having an enantiomeric mixture.

TABLE 1 Representative Compounds # Structure Name  1

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3- (3,5-difluorophenyl)- 5,8-difluoroquinazolin-4(3H)-one 1a: (S)-enantiomer 1b: (R)-enantiomer  2

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5- difluorophenyl)-8- fluoroquinazolin-4(3H)- one2a: (S)-enantiomer 2b: (R)-enantiomer  3

methyl 6-((4-amino- 6-((1-(5-chloro-4- oxo-3-phenyl-3,4-dihydroquinazolin- 2-yl)ethyl)amino) pyrimidin-5- yl)ethynyl)nicotinate3a: (S)-enantiomer 3b: (R)-enantiomer  4

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5,8- difluoro-3- phenylquinazolin- 4(3H)-one 4a:(S)-enantiomer 4b: (R)-enantiomer  5

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8- chloro-3- phenylquinazolin- 4(3H)-one 5a:(S)-enantiomer 5b: (R)-enantiomer  6

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-8-fluoro-3- phenylquinazolin- 4(3H)-one 6a:(S)-enantiomer 6b: (R)-enantiomer  7

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3- (3,5-difluorophenyl)- 5-fluoroquinazolin- 4(3H)-one7a: (S)-enantiomer 7b: (R)-enantiomer  8

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- fluoro-3- phenylquinazolin- 4(3H)-one 8a:(S)-enantiomer 8b: (R)-enantiomer  9

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin-4(3H)-one 9a: (S)-enantiomer 9b: (R)-enantiomer 10

2-(1-((6-amino-5-((5- methoxypyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5,8- dichloro-3- phenylquinazolin- 4(3H)-one 10a:(S)-enantiomer 10b: (R)-enantiomer 11

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)- 5,8-dichloro-3- phenylquinazolin- 4(3H)-one 11a:(S)-enantiomer 11b: (R)-enantiomer 12

2-(1-((6-amino-5-((5- methoxypyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8- fluoro-3- phenylquinazolin- 4(3H)-one 12a:(S)-enantiomer 12b: (R)-enantiomer 13

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8- fluoro-3- phenylquinazolin- 4(3H)-one 13a:(S)-enantiomer 13b: (R)-enantiomer 14

2-(1-((6-amino-5- (pyridazin-3- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 14a:(S)-enantiomer 14b: (R)-enantiomer 15

2-(1-((6-amino-5-((6- aminopyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin-4(3H)-one 15a: (S)-enantiomer 15b: (R)-enantiomer 16

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro-3- phenylquinazolin- 4(3H)-one 16a: (S)-enantiomer 16b:(R)-enantiomer 17

2-(1-((6-amino-5-((6- amino-4-(trifluoro- methyl)pyridin-3-yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro-phenyl)quinazolin- 4(3H)-one 17a: (S)-enantiomer 17b: (R)-enantiomer 18

2-(1-((6-amino-5-((6- amino-4- (trifluoromethyl)pyridin-3-yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin-4(3H)-one 18a: (S)-enantiomer 18b: (R)-enantiomer 19

2-1-((6-amino-5-(3- hydroxybut-1-yn-1- yl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 19a:(S),(R)-diastereomer 19b: (S),(S)-diastereomer 20

2-(1-((6-amino-5-(3- hydroxybut-1-yn-1- yl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one20a: (S),(R)-diastereomer 20b: (S),(S)-diastereomer 23

2-(1-((6-amino-5- (cyclopropylethynyl) pyrimidin-4- yl)amino)ethyl)-5-chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 23a: (S)-enantiomer23b: (R)-enantiomer 24

2-(1-((6-amino-5-(cyclo- propylethynyl)pyrimidin- 4-yl)amino)ethyl)-5-chloro-3- phenylquinazolin- 4(3H)-one 24a: (S)-enantiomer 24b:(R)-enantiomer 25

5-chloro-2-(1-((2,6- diamino-5-(phenyl- ethynyl)pyrimidin-4-yl)amino)ethyl)-3- phenylquinazolin- 4(3H)-one 25a: (S)-enantiomer 25b:(R)-enantiomer 26

2-(1-((6-amino-5-((4- (trifluoromethoxy) phenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin-4(3H)-one 26a: (S)-enantiomer 26b: (R)-enantiomer 27

2-(1-((6-amino-5-((4- (trifluoromethoxy) phenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)- 5-chloro-3- phenylquinazolin- 4(3H)-one 27a:(S)-enantiomer 27b: (R)-enantiomer 28

2-(1-((6-amino-5-(3- hydroxy-3-methylbut-1- yn-1-yl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one28a: (S)-enantiomer 28b: (R)-enantiomer 29

2-(1-((6-amino-5-(3- hydroxy-3- methylbut-1-yn-1- yl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 29a:(S)-enantiomer 29b: (R)-enantiomer 30

2-(1-((6-amino-5- (pyridin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5-methyl-3- phenylquinazolin- 4(3H)-one 30a: (S)-enantiomer 30b:(R)-enantiomer 31

2-(1-((6-amino-5-((6- aminopyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 31a:(S)-enantiomer 31b: (R)-enantiomer 32

2-(1-((6-amino-5-((2- aminopyrimidin-5- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one32a: (S)-enantiomer 32b: (R)-enantiomer 33

2-(1-((6-amino-5-((2- aminopyrimidin-5- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 33a:(S)-enantiomer 33b: (R)-enantiomer 34

2-(1-((6-amino-5-((5- aminopyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one34a: (S)-enantiomer 34b: (R)-enantiomer 35

2-(1-((6-amino-5-((5- aminopyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 35a:(S)-enantiomer 35b: (R)-enantiomer 36

2-(1-(6-amino-5- (pyridin-2- ylethynyl)pyrimidin-4-yl)piperidin-2-yl)-5- chloro-3- phenylquinazolin- 4(3H)-one 36a:(S)-enantiomer 36b: (R)-enantiomer 37

2-(1-(6-amino-5- (pyridin-2- ylethynyl)pyrimidin- 4-yl)pyrrolidin-2-yl)-5-chloro-3- phenylquinazolin- 4(3H)-one 37a: (S)-enantiomer 37b:(R)-enantiomer 38

3-(2-(1-((6-amino-5- (pyridin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-4-oxoquinazolin- 3(4H)-yl)benzamide 38a:(S)-enantiomer 38b: (R)-enantiomer 39

3-(2-(1-((6-amino-5- (pyridin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-4- oxoquinazolin-3(4H)- yl)-N-ethyl-benzenesulfonamide 39a: (S)-enantiomer 39b: (R)-enantiomer 40

3-(2-(1-((6-amino-5- (pyridin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-4-oxoquinazolin- 3(4H)- yl)benzenesulfonamide40a: (S)-enantiomer 40b: (R)-enantiomer 41

2-(1-((6-amino-5- (pyrimidin-5- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin-4(3H)-one 41a: (S)-enantiomer 41b: (R)-enantiomer 42

2-(1-((6-amino-5- (pyrimidin-5- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 42a:(S)-enantiomer 42b: (R)-enantiomer 43

2-(1-((6-amino-5- (pyridin-3- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5-chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 43a: (S)-enantiomer43b: (R)-enantiomer 44

2-(1-((6-amino-5- (pyridin-3- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro-3- phenylquinazolin- 4(3H)-one 44a: (S)-enantiomer 44b:(R)-enantiomer 45

2-(1-((6-amino-5- (pyridin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5-chloro-3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one 45a: (S)-enantiomer45b: (R)-enantiomer 46

2-(1-((6-amino-5-((2- aminobenzo[d]thiazol- 6-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 46a:(S)-enantiomer 46b: (R)-enantiomer 47

2-(1-((6-amino-5-((3- fluoro-5-methoxy- phenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 47a:(S)-enantiomer 47b: (R)-enantiomer 48

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 48a:(S)-enantiomer 48b: (R)-enantiomer 49

2-(1-((5-((1H- pyrazol-4- yl)ethynyl)-6- aminopyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 49a:(S)-enantiomer 49b: (R)-enantiomer 50

2-(1-((6-amino-5- (pyridin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro-3- phenylquinazolin- 4(3H)-one 50a: (S)-enantiomer 50b:(R)-enantiomer 51

2-(1-((6-amino-5-(phenyl- ethynyl)pyrimidin-4- yl)amino)ethyl)-5-chloro-3- phenylquinazolin- 4(3H)-one 51a: (S)-enantiomer 51b:(R)-enantiomer

TABLE 1a Representative Compounds # Structure Name  52

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- hydroxy-3- phenylquinazolin- 4(3H)-one 52a:(S)-enantiomer 52b: (R)-enantiomer  53

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-8-methyl-3- phenylquinazolin-4(3H)- one 53a:(S)-enantiomer 53b: (R)-enantiomer  54

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- methyl-3- phenylquinazolin- 4(3H)-one 54a:(S)-enantiomer 54b: (R)-enantiomer  55

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-4-oxo-3- phenyl-3,4- dihydroquinazoline-5- carbonitrile55a: (S)-enantiomer 55b: (R)-enantiomer  56

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8- methyl-3- phenylquinazolin- 4(3H)-one 56a:(S)-enantiomer 56b: (R)-enantiomer  57

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3- butylphenyl)-5- chloroquinazolin-4(3H)- one 57a:(S)-enantiomer 57b: (R)-enantiomer  58

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-(3- (methylsulfonyl)phenyl)quinazolin-4(3H)-one 58a: (S)-enantiomer 58b: (R)-enantiomer  59

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3- (tert-butyl)phenyl)-5- chloroquinazolin-4(3H)- one59a: (S)-enantiomer 59b: (R)-enantiomer  60

3-([1,1′-biphenyl]-3- yl)-2-(1-((6-amino-5- ((5-fluoropyridin-2-yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-5- chloroquinazolin- 4(3H)-one60a: (S)-enantiomer 60b: (R)-enantiomer  61

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-(3- ethylphenyl)quinazolin- 4(3H)-one 61a:(S)-enantiomer 61b: (R)-enantiomer  62

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8- fluoro-5-methyl-3- phenylquinazolin- 4(3H)-one 62a:(S)-enantiomer 62b: (R)-enantiomer  63

2-(1-((6-amino-5-((3- fluoro-5- methoxyphenyl)ethynyl) pyrimidin-4-yl)amino)ethyl)-5,8- difluoro-3-phenyl- quinazolin-4(3H)-one 63a:(S)-enantiomer 63b: (R)-enantiomer  64

2-(1-((6-amino-5-((3- fluoro-5-methoxy- phenyl)ethynyl) pyrimidin-4-yl)amino)ethyl)-8- fluoro-3- phenylquinazolin- 4(3H)-one 64a:(S)-enantiomer 64b: (R)-enantiomer  65

2-(1-((6-amino-5-((3- fluoro-5- methoxyphenyl)ethynyl) pyrimidin-4-yl)amino)ethyl)-5-fluoro- 3-phenylquinazolin- 4(3H)-one 65a:(S)-enantiomer 65b: (R)-enantiomer  66

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5-(difluoromethyl)-3- (3,5-difluoro- phenyl)quinazolin- 4(3H)-one 66a:(S)-enantiomer 66b: (R)-enantiomer  67

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- (difluoromethyl)-3- phenylquinazolin-4(3H)- one 67a:(S)-enantiomer 67b: (R)-enantiomer  68

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3- phenyl-5-(trifluoro- methyl)quinazolin- 4(3H)-one68a: (S)-enantiomer 68b: (R)-enantiomer  69

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro- 8-methyl-3- phenylquinazolin-4(3H)- one 69a:(S)-enantiomer 69b: (R)-enantiomer  70

3-(2-(1-((6-amino-5- ((5-fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- (difluoromethyl)-4- oxoquinazolin-3(4H)-yl)benzonitrile 70a: (S)-enantiomer 70b: (R)-enantiomer  71

3-(2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5- (difluoromethyl)-4- oxoquinazolin-3(4H)-yl)benzonitrile 71a: (S)-enantiomer 71b: (R)-enantiomer  72

3-(2-(1-((6-amino-5- ((5-fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8- fluoro-5-methyl-4- oxoquinazolin-3(4H)-yl)benzonitrile 72a: (S)-enantiomer 72b: (R)-enantiomer  73

3-(2-(1-((6-amino-5- (pyrazin-2- ylethyny)pyrimidin-4-yl)amino)ethyl)-8-fluoro- 5-methyl-4- oxoquinazolin-3(4H)-yl)benzonitrile 73a: (S)-enantiomer 73b: (R)-enantiomer  74

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)propyl)-5-(difluoromethyl)-3- (3,5-difluoro- phenyl)quinazolin- 4(3H)-one 74a:(S)-enantiomer 74b: (R)-enantiomer  75

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro- 5-methyl-3- phenylquinazolin-4(3H)- one 75a:(S)-enantiomer 75b: (R)-enantiomer  76

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5-(difluoromethyl)-3- phenylquinazolin- 4(3H)-one 76a: (S)-enantiomer 76b:(R)-enantiomer  77

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- (difluoromethyl)-3- (3,5-difluoro- phenyl)quinazolin-4(3H)-one 77a: (S)-enantiomer 77b: (R)-enantiomer  78

5-chloro-2-(1-((2,6- diamino-5-((5- fluoropyridin-2-yl)ethynyl)pyrimidin- 4-yl)amino)ethyl)-3- (3,5-difluoro-phenyl)quinazolin- 4(3H)-one 78a: (S)-enantiomer 78b: (R)-enantiomer  79

2-(1-((6-amino-5-((3- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 79a:(S)-enantiomer 79b: (R)-enantiomer  80

2-(1-((6-amino-5-((3- methoxypyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 80a:(S)-enantiomer 80b: (R)-enantiomer  81

2-(1-((6-amino-5-((3- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-(3-methoxy-2- methylphenyl)quinazolin-4(3H)-one 81a: (S)-enantiomer 81a-1 and a-2: atropisomers 81b:(R)-enantiomer 81b-1 and b-2: atropisomers  82

2-(1-((6-amino-5- ((3,5-difluoropyridin- 2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 82a:(S)-enantiomer 82b: (R)-enantiomer  83

5-chloro-2-(1-((2,6- diamino-5-((5- fluoropyridin-2-yl)ethynyl)pyrimidin-4- yl)amino)ethyl)-3- phenylquinazolin-4(3H)- one83a: (S)-enantiomer 83b: (R)-enantiomer  84

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-(3,5- difluorophenyl)-8- fluoroquinazolin-4(3H)-one 84a: (S)-enantiomer 84b: (R)-enantiomer  85

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one85a: (S)-enantiomer 85b: (R)-enantiomer  86

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5-fluoro-3- phenylquinazolin- 4(3H)-one 86a: (S)-enantiomer 86b:(R)-enantiomer  87

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5- difluorophenyl)-5- fluoroquinazolin-4(3H)- one87a: (S)-enantiomer 87b: (R)-enantiomer  89

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-(3- chlorophenyl)quinazolin- 4(3H)-one 89a:(S)-enantiomer 89b: (R)-enantiomer  90

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-6- fluoro-3- phenylquinazolin- 4(3H)-one 90a:(S)-enantiomer 90b: (R)-enantiomer  91

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-6-fluoro- 3-phenylquinazolin- 4(3H)-one 91a:(S)-enantiomer 91b: (R)-enantiomer  92

3-(2-(1-((6-amino-5- ((5-fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-4- oxoquinazolin-3(4H)- yl)benzonitrile 92a:(S)-enantiomer 92b: (R)-enantiomer  93

3-(2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 4-oxoquinazolin-3(4H)- yl)benzonitrile 93a:(S)-enantiomer 93b: (R)-enantiomer  94

3-(2-(1-((6-amino-5- ((5-fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-6- fluoro-4- oxoquinazolin-3(4H)- yl)benzonitrile 94a:(S)-enantiomer 94b: (R)-enantiomer  95

3-(2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-6-fluoro- 4-oxoquinazolin-3(4H)- yl)benzonitrile 95a:(S)-enantiomer 95b: (R)-enantiomer  96

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3- (3-chlorophenyl)-6- fluoroquinazolin- 4(3H)-one96a: (S)-enantiomer 96b: (R)-enantiomer  97

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3- chlorophenyl)-6- fluoroquinazolin-4(3H)- one 97a:(S)-enantiomer 97b: (R)-enantiomer  98

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5-methyl-3- phenylquinazolin- 4(3H)-one 98a: (S)-enantiomer 98b:(R)-enantiomer  99

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro- 3-(3- fluorophenyl)quinazolin- 4(3H)-one 99a:(S)-enantiomer 99b: (R)-enantiomer 100

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-3-(3,5-difluorophenyl)- 8-fluoroquinazolin- 4(3H)-one 100a: (S)-enantiomer100b: (R)-enantiomer 101

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro- 3-(3- fluorophenyl)quinazolin- 4(3H)-one 101a:(S)-enantiomer 101b: (R)-enantiomer 102

2-(1-((6-amino-5- (pyrimidin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 102a:(S)-enantiomer 102b: (R)-enantiomer 103

2-(1-((6-amino-5- (pyrimidin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-(3,5-difluoro- phenyl)quinazolin- 4(3H)-one103a: (S)-enantiomer 103b: (R)-enantiomer 104

2-(1-((6-amino-5- (pyrimidin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5- methyl-3- phenylquinazolin- 4(3H)-one 104a:(S)-enantiomer 104b: (R)-enantiomer 105

2-(1-((6-amino-5- (pyrimidin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5- difluorophenyl)-5- methylquinazolin-4(3H)- one105a: (S)-enantiomer 105b: (R)-enantiomer 106

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-3-(3-fluorophenyl)-5- methylquinazolin- 4(3H)-one 106a: (S)-enantiomer106b: (R)-enantiomer 107

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4-yl)amino)propyl)-3-(3,5- difluorophenyl)-5- fluoroquinazolin-4(3H)- one107a: (S)-enantiomer 107b: (R)-enantiomer 108

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)propyl)-3-(3,5- difluorophenyl)-5- methylquinazolin- 4(3H)-one 108a:(S)-enantiomer 108b: (R)-enantiomer 109

2-(1-((6-amino-5- (pyrimidin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro- 3-phenylquinazolin- 4(3H)-one 109a:(S)-enantiomer 109b: (R)-enantiomer 110

3-(2-(1-((6-amino-5- (phenylethynyl)pyrimidin- 4-yl)amino)ethyl)-5-fluoro-4- oxoquinazolin-3(4H)- yl)benzonitrile 110a: (S)-enantiomer110b: (R)-enantiomer 111

2-(1-((6-amino-5- (phenylethynyl)pyrimidin- 4-yl)amino)ethyl)-5-fluoro-3-(3- fluorophenyl)quinazolin- 4(3H)-one 111a: (S)-enantiomer111b: (R)-enantiomer 112

2-(1-((6-amino-5- (phenylethynyl)pyrimidin- 4-yl)amino)ethyl)-5-(methylsulfonyl)-3- phenylquinazolin- 4(3H)-one 112a: (S)-enantiomer112b: (R)-enantiomer 113

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5-(methylsulfonyl)-3- phenylquinazolin-4(3H)- one 113a: (S)-enantiomer113b: (R)-enantiomer 114

2-(1-((6-amino-5- (phenylethynyl)pyrimidin- 4-yl)amino)ethyl)-4-oxo-3-phenyl-3,4- dihydroquinazoline- 5-carbonitrile 114a:(S)-enantiomer 114b: (R)-enantiomer 115

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro- 3-(pyridin-3- yl)quinazolin-4(3H)-one 115a:(S)-enantiomer 115b: (R)-enantiomer 116

2-(1-((6-amino-5- (phenylethynyl)pyrimidin- 4-yl)amino)ethyl)-5-fluoro-3-(pyridin-3- yl)quinazolin-4(3H)- one 116a: (S)-enantiomer 116b:(R)-enantiomer 117

2-(1-((6-amino-5- (pyrimidin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-(pyridin-3- yl)quinazolin-4(3H)-one 117a:(S)-enantiomer 117b: (R)-enantiomer 118

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5-chloro-3-(pyridin-3- yl)quinazolin-4(3H)- one 118a: (S)-enantiomer 118b:(R)-enantiomer 119

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4- yl)amino)ethyl)-5-methyl-3-(pyridin-3- yl)quinazolin-4(3H)-one 119a: (S)-enantiomer 119b:(R)-enantiomer 120

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-3-(5-fluoropyridin-3- yl)-5- methylquinazolin- 4(3H)-one 120a:(S)-enantiomer 120b: (R)-enantiomer 121

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-morpholinoquinazolin- 4(3H)-one 121a:(S)-enantiomer 121b: (R)-enantiomer 122

2-(1-((6-amino-5-((3- fluoro-5-methoxy- phenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- morpholinoquinazolin- 4(3H)-one 122a:(S)-enantiomer 122b: (R)-enantiomer 123

N-(3-(2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 4-oxoquinazolin-3(4H)- yl)benzyl)methane-sulfonamide 123a: (S)-enantiomer 123b: (R)-enantiomer 124

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-5-chloro-3-((1R,5S)-8- methyl-8- azabicyclo[3.2.1]octan- 3-yl)quinazolin-4(3H)-one 124a: (S)-enantiomer 124b: (R)-enantiomer 125

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3- yl)quinazolin-4(3H)-one 125a: (S)-enantiomer125b: (R)-enantiomer 126

2-(1-((6-amino-5- (pyrazin-2- ylethynyl)pyrimidin- 4-yl)amino)ethyl)-3-(azepan-1-yl)-5- chloroquinazolin- 4(3H)-one 126a: (S)-enantiomer 126b:(R)-enantiomer 127

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-(piperazin-1- yl)quinazolin-4(3H)-one 127a:(S)-enantiomer 127b: (R)-enantiomer 128

N-(3-(2-(1-((6- amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- methyl-4- oxoquinazolin-3(4H)- yl)benzyl)-N-methyl-methanesulfonamide 128a: (S)-enantiomer 128b: (R)-enantiomer 129

(S)-N-(3-(2-(1-((6- amino-5-((5- fluoropyridin-2-yl)ethynyl)pyrimidin-4- yl)(methyl)amino)ethyl)- 5-chloro-4-oxoquinazolin-3(4H)- yl)benzyl)-N-methyl- methanesulfonamide 129a:(S)-enantiomer 129b: (R)-enantiomer 130

N-(3-(2-(1-((6- amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-4-oxoquinazolin- 3(4H)-yl)benzyl)methanesulfonamide 130a: (S)-enantiomer 130b: (R)-enantiomer 131

N-(3-(2-(1-((6-amino-5- ((5-fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 4-oxoquinazolin-3(4H)- yl)benzyl)-2-methylpropane-1- sulfonamide 131a: (S)-enantiomer 131b: (R)-enantiomer132

2-(1-((6-amino-5-((5- (trifluoromethyl)pyridin- 2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 132a:(S)-enantiomer 132b: (R)-enantiomer 133

2-(1-((6-amino-5-((5- methylpyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 133a:(S)-enantiomer 133b: (R)-enantiomer 134

2-(1-((6-amino-5-((5- (trifluoromethyl)pyridin- 2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin-4(3H)-one 134a: (S)-enantiomer 134b: (R)-enantiomer 135

6-((4-amino-6-((1-(5- chloro-4-oxo-3-phenyl- 3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin- 5-yl)ethynyl)nicotinamide 135a: (S)-enantiomer135b: (R)-enantiomer 136

6-((4-amino-6-((1-(5- chloro-3-(3,5- difluorophenyl)-4- oxo-3,4-dihydro-quinazolin-2-yl)ethyl) amino)pyrimidin-5- yl)ethynyl)nicotinamide 136a:(S)-enantiomer 136b: (R)-enantiomer 137

isopropyl 6-((4-amino-6- ((1-(5-chloro-4-oxo-3- phenyl-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidin- 5-yl)ethynyl)nicotinate137a: (S)-enantiomer 137b: (R)-enantiomer 138

6-((4-amino-6-((1-(5- chloro-4-oxo-3- phenyl-3,4- dihydroquinazolin-2-yl)ethyl)amino)pyrimidin- 5-yl)ethynyl)nicotinic acid 138a:(S)-enantiomer 138b: (R)-enantiomer 139

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)-2- hydroxyethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 139a:(S)-enantiomer 139b: (R)-enantiomer 140

2-(1-((6-amino-5-((5- fluoro-6- methylpyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 140a:(S)-enantiomer 140b: (R)-enantiomer 141

2-(1-((6-amino-5-((6- methylpyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 141a:(S)-enantiomer 141b: (R)-enantiomer 142

2-(1-((6-amino-5-((3- (trifluoromethyl)pyridin- 2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 142a:(S)-enantiomer 142b: (R)-enantiomer 143

2-(1-((6-amino-5-((3- methylpyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 143a:(S)-enantiomer 143b: (R)-enantiomer 144

2-(1-((6-amino-5- (cyclopentylethynyl) pyrimidin-4- yl)amino)ethyl)-5-chloro-3- phenylquinazolin- 4(3H)-one 144a: (S)-enantiomer 144b:(R)-enantiomer 145

2-(1-((6-amino-5- (cyclohexylethynyl) pyrimidin-4-yl)amino)ethyl)-5-chloro-3- phenylquinazolin-4(3H)- one 145a: (S)-enantiomer145b: (R)-enantiomer 146

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)-2- methoxyethyl)-5- chloro-3-(3,5-difluoro-phenyl)quinazolin- 4(3H)-one 146a: (S)-enantiomer 146b: (R)-enantiomer147

2-(1-((6-amino-5-((4- methylpyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 147a:(S)-enantiomer 147b: (R)-enantiomer 148

2-(1-((6-amino-5-((4- (trifluoromethyl)pyridin- 2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 148a:(S)-enantiomer 148b: (R)-enantiomer 149

2-(1-((6-amino-5-((4- (difluoromethyl)pyridin- 2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-phenyl- quinazolin-4(3H)-one 149a:(S)-enantiomer 149b: (R)-enantiomer 150

2-(1-((6-amino-5-((4- ethylpyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 150a:(S)-enantiomer 150b: (R)-enantiomer 151

2-(1-((6-amino-5-((6- (trifluoromethyl)pyridin- 2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-phenyl- quinazolin-4(3H)-one 151a:(S)-enantiomer 151b: (R)-enantiomer 152

2-(1-((5-((3- acetylpyridin-2- yl)ethynyl)-6- aminopyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 152a:(S)-enantiomer 152b: (R)-enantiomer 153

2-(1-((5-((6- acetylpyridin-2- yl)ethynyl)-6- aminopyrimidin-4-yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 153a:(S)-enantiomer 153b: (R)-enantiomer 154

2-(1-((6-amino-5-((4- (hydroxymethyl)pyridin- 2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 154a:(S)-enantiomer 154b: (R)-enantiomer 155

2-(1-((6-amino-5-((6- (hydroxymethyl)pyridin- 2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-phenyl- quinazolin-4(3H)-one 155a:(S)-enantiomer 155b: (R)-enantiomer 156

2-((4-amino-6-((1-(5- chloro-4-oxo-3- phenyl-3,4- dihydroquinazolin-2-yl)ethyl)amino) pyrimidin-5-yl) ethynyl)isonicotinamide 156a:(S)-enantiomer 156b: (R)-enantiomer 157

2-(1-((6-amino-5-((6-(1- hydroxyethyl)pyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 157a:(S)-enantiomer 157b: (R)-enantiomer 158

methyl 2-((4-amino- 6-((1-(5-chloro-4- oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidin-5-yl)ethynyl)isonicotinate 158a: (S)-enantiomer 158b: (R)-enantiomer 159

2-(1-((6-amino-5-((6- (aminomethyl)pyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 159a:(S)-enantiomer 159b: (R)-enantiomer 160

2-((4-amino-6-((1-(5- chloro-4-oxo-3- phenyl-3,4- dihydroquinazolin-2-yl)ethyl)amino)pyrimidin- 5-yl)ethynyl)isonicotinic acid 160a:(S)-enantiomer 160b: (R)-enantiomer 161

2-(1-((5-((3- acetylphenyl)ethynyl)-6- aminopyrimidin-4-yl)amino)ethyl)-5-chloro- 3-phenylquinazolin- 4(3H)-one 161a:(S)-enantiomer 161b: (R)-enantiomer 162

2-(1-((6-amino-5-((3- (hydroxymethyl)phenyl) ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3- phenylquinazolin- 4(3H)-one 162a:(S)-enantiomer 162b: (R)-enantiomer 163

2-(1-((6-amino-5-((3- (hydroxymethyl)pyridin- 2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-phenyl- quinazolin-4(3H)-one 163a:(S)-enantiomer 163b: (R)-enantiomer 164

2-(1-((6-amino-5-((5- methylpyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5- chloro-3-(3,5-difluoro- phenyl)quinazolin-4(3H)-one 164a: (S)-enantiomer 164b: (R)-enantiomer 165

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-(3- ((methylamino)methyl) phenyl)quinazolin-4(3H)-one 165a: (S)-enantiomer 165b: (R)-enantiomer 166

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3- (azetidin-3-yl)-5- chloroquinazolin- 4(3H)-one166a: (S)-enantiomer 166b: (R)-enantiomer 167

2-(1-((6-amino-5-((5- fluoropyridin-2- yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro- 3-(tetrahydro-2H-pyran- 4-yl)quinazolin-4(3H)-one 167a: (S)-enantiomer 167b: (R)-enantiomer

Provided are also compounds of formula (I), (IA), (IB), (IC), or (II),or pharmaceutically acceptable salts, prodrugs, or solvates thereof, inwhich from 1 to n hydrogen atoms attached to a carbon atom may bereplaced by a deuterium atom or D, in which n is the number of hydrogenatoms in the molecule. As known in the art, the deuterium atom is anon-radioactive isotope of the hydrogen atom. Such compounds mayincrease resistance to metabolism, and thus may be useful for increasingthe half-life of the compounds of formula (I), (IA), (IB), (IC), or(II), or pharmaceutically acceptable salts, prodrugs, or solvatesthereof, when administered to a mammal. See, e.g., Foster, “DeuteriumIsotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci.,5(12):524-527 (1984). Such compounds are synthesized by means well knownin the art, for example by employing starting materials in which one ormore hydrogen atoms have been replaced by deuterium.

Provided are also pharmaceutically acceptable salts, hydrates, solvates,tautomeric forms, polymorphs, and prodrugs of the compounds of formula(I), (IA), (IB), (IC), or (II).

“Pharmaceutically acceptable salts” include, for example, salts withinorganic acids and salts with an organic acid. In addition, if thecompounds described herein are obtained as an acid addition salt, thefree base can be obtained by basifying a solution of the acid salt.Conversely, if the product is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare nontoxic pharmaceutically acceptable additionsalts.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds of formula (I), (IA), (IB), (IC), or(II) are also provided. Hydrates of the compounds of formula (I), (IA),(IB), (IC), or (II) are also provided.

A “prodrug” includes any compound that becomes a compound of formula(I), (IA), (IB), (IC), or (II) when administered to a subject, e.g.,upon metabolic processing of the prodrug.

In certain embodiments, provided are optical isomers, racemates, orother mixtures thereof, of the compounds of formula (I), (IA), (IB),(IC), or (II), or pharmaceutically acceptable salts, prodrugs, orsolvates thereof. In those situations, the single enantiomer ordiastereomer, i.e., optically active form, can be obtained by asymmetricsynthesis or by resolution of the racemate. Resolution of racemates canbe accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral high pressure liquid chromatography (HPLC)column. In addition, provided are also Z- and E-forms (or cis- andtrans-forms) of the compounds of formula (I), (IA), (IB), (IC), or (II),or pharmaceutically acceptable salts, prodrugs, or solvates thereof withcarbon-carbon double bonds. Provided are also all tautomeric forms ofthe compounds of formula (I), (IA), (IB), (IC), or (II), orpharmaceutically acceptable salts, prodrugs, or solvates thereof.

Compositions provided herein that include a compound of formula (I),(IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt,prodrug, or solvate thereof, may include racemic mixtures, or mixturescontaining an enantiomeric excess of one enantiomer or singlediastereomers or diastereomeric mixtures. All such isomeric forms ofthese compounds are expressly included herein the same as if each andevery isomeric form were specifically and individually listed.

In certain embodiments, provided herein are also crystalline andamorphous forms of the compounds of formula (I), (IA), (IB), (IC), or(II), or pharmaceutically acceptable salts, prodrugs, or solvatesthereof.

In certain embodiments, provided are also chelates, non-covalentcomplexes, and mixtures thereof, of the compounds of formula (I), (IA),(IB), (IC), or (II), or pharmaceutically acceptable salts, prodrugs, orsolvates thereof. A “chelate” is formed by the coordination of acompound to a metal ion at two (or more) points. A “non-covalentcomplex” is formed by the interaction of a compound and another moleculewherein a covalent bond is not formed between the compound and themolecule. For example, complexation can occur through van der Waalsinteractions, hydrogen bonding, and electrostatic interactions (alsocalled ionic bonding).

Therapeutic Uses of the Compounds

The compounds of formula (I), (IA), (IB), (IC), or (II), or apharmaceutically acceptable salt, prodrug, or solvate thereof may beused for the treatment of diseases and/or conditions mediated by PI3Kisomers, such as PI3Kδ. Thus, provided herein are methods for inhibitingone or more PI3K isomers. In one embodiment, provided are methods forinhibiting PI3Kδ activity using a compound of formula (I), (IA), (IB),(IC), or (II), or a pharmaceutically acceptable salt, prodrug, orsolvate thereof. The PI3K isomers may be selectively or specificallyinhibited. Additionally, the compounds may be used to inhibit MKactivity therapeutically or prophylactically.

In some embodiments, the methods include administering a compound offormula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptablesalt, prodrug, or solvate thereof, in a therapeutically effective amountto a subject (including a human) in need thereof. The method can beemployed to treat a subject who has or is believed to have a disease orcondition whose symptoms or pathology is mediated by PI3Kδ expression oractivity.

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following:

a) inhibiting the disease or condition (e.g., decreasing one or moresymptoms resulting from the disease or condition, and/or diminishing theextent of the disease or condition);

b) slowing or arresting the development of one or more clinical symptomsassociated with the disease or condition (e.g., stabilizing the diseaseor condition, preventing or delaying the worsening or progression of thedisease or condition, and/or preventing or delaying the spread (e.g.,metastasis) of the disease or condition); and/or

c) relieving the disease, that is, causing the regression of clinicalsymptoms (e.g., ameliorating the disease state, providing partial ortotal remission of the disease or condition, enhancing effect of anothermedication, delaying the progression of the disease, increasing thequality of life, and/or prolonging survival.

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In one embodiment, the subject is a human.

The term “therapeutically effective amount” of a compound of formula(I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt,prodrug, or solvate thereof, means an amount sufficient to effecttreatment when administered to a subject, to provide a therapeuticbenefit such as amelioration of symptoms or slowing of diseaseprogression. For example, a therapeutically effective amount may be anamount sufficient to decrease a symptom of a disease or conditionresponsive to inhibition of PI3Kδ activity. The therapeuticallyeffective amount may vary depending on the subject, and disease orcondition being treated, the weight and age of the subject, the severityof the disease or condition, and the manner of administering, which canreadily be determined by one or ordinary skill in the art.

The term “inhibition” indicates a decrease in the baseline activity of abiological activity or process. “Inhibition of activity of PI3K isomers”or variants thereof refer to a decrease in activity in any PI3K isomer(e.g., alpha, beta, gamma, or delta) as a direct or indirect response tothe presence of a compound of formula (I), (IA), (IB), (IC), or (II), ora pharmaceutically acceptable salt, prodrug, or solvent thereof,relative to the activity of PI3K isomer in the absence of the compoundof formula (I), (IA), (IB), (IC), or (II), or a pharmaceuticallyacceptable salt, prodrug, or solvent thereof. “Inhibition of PI3Kδactivity” or variants thereof refer to a decrease in PI3Kδ activity as adirect or indirect response to the presence of a compound of formula(I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt,prodrug, or solvate thereof, relative to the activity of PI3Kδ in theabsence of the compound of formula (I), (IA), (IB), (IC), or (II), or apharmaceutically acceptable salt, prodrug, or solvate thereof. In someembodiments, the inhibition of PI3Kδ activity may be compared in thesame subject prior to treatment, or other subjects not receiving thetreatment.

Without wishing to be bound to any theory, the decrease in PI3Kδactivity may be due to the direct interaction of the compound withPI3Kδ, or due to the interaction of the compounds described herein withone or more other factors that in turn affect PI3Kδ activity. Forexample, the presence of the compounds of formula (I), (IA), (IB), (IC),or (II), or a pharmaceutically acceptable salt, prodrug, or solvatethereof, may decrease PI3Kδ activity by directly binding to the PI3Kδ,by causing (directly or indirectly) another factor to decrease PI3Kδactivity, or by (directly or indirectly) decreasing the amount of PI3Kδpresent in the cell or organism.

The terms “PI3K isoform selective inhibitor” generally refers to acompound that inhibits the activity of one or more PI3K isoforms moreeffectively than the other remaining PI3K isoforms. By way of example,the term “PI3Kδ selective inhibitor” generally refers to a compound thatinhibits the activity of the PI3Kδ isoform more effectively than otherisoforms of the PI3K family (e.g., PI3K α, β, or γ).

The relative efficacies of compounds as inhibitors of an enzyme activity(or other biological activity) can be established by determining theconcentrations at which each compound inhibits the activity to apredefined extent and then comparing the results. In one embodiment, theefficacy of a compound as an inhibitor of one or more PI3K isoforms canbe measured by the concentration that inhibits 50% of the activity in abiochemical assay, i.e., the 50% inhibitory concentration or “IC₅₀”.IC₅₀ determinations can be accomplished using conventional techniquesknown in the art, including the techniques describes in the Examplesbelow. In general, an IC₅₀ can be determined by measuring the activityof a given enzyme in the presence of a range of concentrations of thecompound under study. The experimentally obtained values of enzymeactivity may then be plotted against the compound concentrations used.The concentration of the inhibitor that shows 50% enzyme activity (ascompared to the activity in the absence of any inhibitor) is taken asthe IC₅₀ value. Analogously, other inhibitory concentrations can bedefined through appropriate determinations of activity. For example, insome settings it may be desirable to establish a 90% inhibitoryconcentration, i.e., IC₉₀.

In one embodiment, a PI3Kδ selective inhibitor is a compound thatexhibits a 50% inhibitory concentration (IC₅₀) with respect to PI3Kδthat is at least 10-fold, in another aspect at least 20-fold, and inanother aspect at least 30-fold, lower than the IC₅₀ value with respectto any or all of the other Class I PI3K family members. In anotherembodiment, a PI3Kδ selective inhibitor is a compound that exhibits anIC₅₀ with respect to PI3Kδ that is at least 50-fold, in another aspectat least 100-fold, in an additional aspect at least 200-fold, and in yetanother aspect at least 500-fold, lower than the IC₅₀ with respect toany or all of the other PI3K Class I family members. A PI3Kδ selectiveinhibitor is typically administered in an amount such that itselectively inhibits PI3Kδ activity, as described above.

The methods described herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods described herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine, and saliva. Exemplary tissue samples includetumors and biopsies thereof. In this context, the invention may be usedfor a variety of purposes, including therapeutic and experimentalpurposes. For example, the invention may be used ex vivo to determinethe optimal schedule and/or dosing of administration of a PI3Kδselective inhibitor for a given indication, cell type, individual, andother parameters. Information gleaned from such use may be used forexperimental purposes or in the clinic to set protocols for in vivotreatment. Other ex vivo uses for which the invention may be suited aredescribed below or will become apparent to those skilled in the art. Theselected compounds of formula (I), (IA), (IB), (IC), or (II), or apharmaceutically acceptable salt, prodrug, or solvate thereof, may befurther characterized to examine the safety or tolerance dosage in humanor non-human subjects. Such properties may be examined using commonlyknown methods to those skilled in the art.

Compared to other PI3K isoforms, PI3Kδ is generally expressed inhematopoietic cells. Consequently, the direct effects of selectiveinhibitors of PI3Kδ can be observed in hematopoietic cells.Hematopoietic cells typically differentiate into either lymphoidprogenitor cells or myeloid progenitor cells, both of which ultimatelydifferentiate into various mature cell types including leukocytes.Aberrant proliferation of hematopoietic cells of one type ofteninterferes with the production or survival of other hematopoietic celltypes, which can result in compromised immunity, anemia, and/orthrombocytopenia. The methods described herein may treat aberrantproliferation of hematopoietic cells by inhibiting aberrantproliferation of hematopoietic cells. As a result, these methods mayalso ameliorate the symptoms and secondary conditions that result from aprimary effect such as excessive system or localized levels ofleukocytes or lymphocytes.

In some embodiments, the compounds described herein may be used to treatsubjects having various disease states, disorders, and conditions (alsocollectively referred to as “indications”) involving aberrantproliferation of hematopoietic cells (including excessive production oflymphoid progenitor cell-derived cells and/or myeloid progenitorcell-derived cells). Such indications may include, for example,leukemias, lymphomas, myeloproliferative disorders, myelodysplasticsyndromes, and plasma cell neoplasms. In certain embodiments, thecompounds described herein may be used to treat hematologicmalignancies, inflammation, autoimmune disorders, allergic conditions,cardiovascular disease, and autoimmune diseases. In certain embodiments,allergic conditions may include all forms of hypersensitivity.

In other embodiments, the compounds described herein may be used totreat cancers that are mediated by, dependent on or associated with PI3Kactivity, such as PI3Kδ activity. In certain embodiments, the disease isa hematologic malignancy. In certain embodiments, the disease islymphoma, multiple myeloma, or leukemia. In particular embodiments, thehematologic malignancy is leukemia or lymphoma. In specific embodiments,the disease is acute lymphocytic leukemia (ALL), acute myeloid leukemia(AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma(SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD),chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML),multiple myeloma (MM), Hodgkin lymphoma, indolent non-Hodgkin's lymphoma(iNHL), refractory iNHL, non-Hodgkin's lymphoma (NHL), mantle celllymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia(WM), minimal residual disease (MRD), T-cell lymphoma, B-cell lymphoma,diffuse large B-cell lymphoma (DLBCL), T-cell acute lymphoblasticleukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL),lymphoplasmacytic lymphoma, marginal zone lymphoma, or Burkitt lymphoma.In one embodiment, the disease is T-cell acute lymphoblastic leukemia(T-ALL), or B-cell acute lymphoblastic leukemia (B-ALL). It should beunderstood that the non-Hodgkin lymphoma may, in certain embodiments,encompass the indolent B-cell diseases that include, for example,follicular lymphoma, lymphoplasmacytic lymphoma, Waldenstrommacroglobulinemia, and marginal zone lymphoma, as well as the aggressivelymphomas that include, for example, Burkitt lymphoma, diffuse largeB-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).

In other embodiments, the disease is a solid tumor. In particularembodiments, the solid tumor is from pancreatic cancer, bladder cancer,colorectal cancer, breast cancer, prostate cancer, renal cancer,hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer,gastric cancer, esophageal cancer, head and neck cancer, melanoma,neuroendocrine cancers, CNS cancers, brain tumors (e.g., glioma,anaplastic oligodendroglioma, adult glioblastoma multiforme, and adultanaplastic astrocytoma), bone cancer, or soft tissue sarcoma. In someembodiments, the solid tumor is from non-small cell lung cancer,small-cell lung cancer, colon cancer, CNS cancer, melanoma, ovariancancer, renal cancer, prostate cancer, or breast cancer.

In some embodiments, the disease is an autoimmune disease. In particularembodiments, the autoimmune disease is systemic lupus erythematosus(SLE), myestenia gravis, rheumatoid arthritis (RA), acute disseminatedencephalomyelitis, idiopathic thrombocytopenic purpura, multiplesclerosis (MS), Sjoegren's syndrome, psoriasis, autoimmune hemolyticanemia, asthma, or chronic obstructive pulmonary disease (COPD). Inother embodiments, the disease is inflammation. In yet otherembodiments, the disease is excessive or destructive immune reactions,such as asthma, rheumatoid arthritis, multiple sclerosis, chronicobstructive pulmonary disease (COPD), and lupus.

Provided is a method for treating a subject, who has or is suspected ofhaving a disease or condition responsive or believed to be responsive tothe inhibition of PI3Kδ activity by administering to the subject acompound of formula (I), (IA), (IB), (IC), or (II), or apharmaceutically acceptable salt, prodrug, or solvate thereof.

Provided is also a method of inhibiting kinase activity of aphosphatidylinositol 3-kinase delta polypeptide by contacting thepolypeptide with a compound of formula (I), (IA), (IB), (IC), or (II),or a pharmaceutically acceptable salt, prodrug, or solvate thereof. Alsoprovided is a method for increasing sensitivity of cancer cells tochemotherapy, comprising administering to a patient undergoingchemotherapy with a chemotherapeutic agent an amount a compound offormula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptablesalt, prodrug, or solvate thereof, sufficient to increase thesensitivity of cancer cells to the chemotherapeutic agent. In someembodiments, the cancers cells are of hematopoietic origin.

Combination Therapies

In one embodiment, the compounds of the present application (e.g., acompound of formula (I), (IA), (IB), (IC), or (II), or apharmaceutically acceptable salt, prodrug, or solvate thereof) may beused in combination with one or more additional therapeutic agent thatare being used and/or developed to treat cancers or inflammatorydisorders. The one or more additional therapeutic agent may be aninhibitor to PI3K such as PI3Kγ, PI3Kβ, and/or PI3Kα, Janus kinase (JAK)such as JAK1, JAK2 and/or JAK3, spleen tyrosine kinase (SYK), Bruton'styrosine kinase (BTK), bromodomain containing protein inhibitor (BRD)such as BRD4, a lysyl oxidase protein (LOX), lysyl oxidase-like protein(LOXL) such as LOXL1-5, matrix metalloprotease (MMP) such as MMP 1-10,adenosine A2B receptor (A2B), isocitrate dehydrogenase (IDH) such asIDH1, apoptosis signal-regulating kinase (ASK) such as ASK1,serine/threonine kinase TPL2, discoidin domain receptor (DDR) such asDDR1 and DDR2, histone deacetylase (HDAC), protein kinase C (PKC), orany combination thereof.

One, two, three, or more of the therapeutic agents (e.g. a PI3Kinhibitor, a JAK inhibitor, a SYK inhibitor, a BTK inhibitor, a BRD4inhibitor, a LOXL2 inhibitor, a MMP9 inhibitor, a A2B inhibitor, an IDHinhibitor, an ASK inhibitor, a TPL2 inhibitor, a DDR1 inhibitor, a TBKinhibitor, a HDAC inhibitor, a PKC inhibitor) may be further used orcombined with a chemotherapeutic agent, an immunotherapeutic agent, aradiotherapeutic agent, an anti-neoplastic agent, an anti-cancer agent,an anti-fibrotic agent, an anti-angiogenic agent, a therapeuticantibody, or any combination thereof.

Chemotherapeutic agents may be categorized by their mechanism of actioninto, for example, the following groups: anti-metabolites/anti-canceragents, such as pyrimidine analogs (floxuridine, capecitabine, andcytarabine); purine analogs, folate antagonists and related inhibitorsantiproliferative/antimitotic agents including natural products such asvinca alkaloid (vinblastine, vincristine) and microtubule such as taxane(paclitaxel, docetaxel), vinblastin, nocodazole, epothilones andnavelbine, epidipodophyllotoxins (etoposide, teniposide); DNA damagingagents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil,cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin,doxorubicin, epirubicin, iphosphamide, melphalan, merchlorehtamine,mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere,teniposide, etoposide, triethylenethiophosphoramide); antibiotics suchas dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin),idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin; enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents;antiproliferative/antimitotic alkylating agents such as nitrogenmustards cyclophosphamide and analogs, melphalan, chlorambucil), and(hexamethylmelamine and thiotepa), alkyl nitrosoureas (BCNU) andanalogs, streptozocin), trazenes-dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate); platinum coordination complexes (cisplatin,oxiloplatinim, carboplatin), procarbazine, hydroxyurea, mitotane,aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen,goserelin, bicalutamide, nilutamide) and aromatase inhibitors(letrozole, anastrozole); anticoagulants (heparin, synthetic heparinsalts and other inhibitors of thrombin); fibrinolytic agents (such astissue plasminogen activator, streptokinase and urokinase), aspirin,dipyridamole, ticlopidine, clopidogrel; antimigratory agents;antisecretory agents (breveldin); immunosuppressives tacrolimussirolimus azathioprine, mycophenolate; compounds (TNP-470, genistein)and growth factor inhibitors (vascular endothelial growth factorinhibitors, fibroblast growth factor inhibitors); angiotensin receptorblocker, nitric oxide donors; anti-sense oligonucleotides; antibodies(trastuzumab, rituximab); cell cycle inhibitors and differentiationinducers (tretinoin); inhibitors, topoisomerase inhibitors (doxorubicin(adriamycin), daunorubicin, dactinomycin, eniposide, epirubicin,etoposide, idarubicin, irinotecan and mitoxantrone, topotecan,irinotecan, camptothesin), corticosteroids (cortisone, dexamethasone,hydrocortisone, methylpednisolone, prednisone, and prenisolone); growthfactor signal transduction kinase inhibitors; dysfunction inducers,toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetellapertussis adenylate cyclase toxin, or diphtheria toxin, and caspaseactivators; and chromatin.

As used herein the term “chemotherapeutic agent” or “chemotherapeutic”(or “chemotherapy,” in the case of treatment with a chemotherapeuticagent) may encompass any non-proteinaceous (e.g., non-peptidic) chemicalcompound useful in the treatment of cancer. Examples of chemotherapeuticagents include alkylating agents such as thiotepa and cyclophosphamide(CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines such as benzodopa, carboquone, meturedopa, anduredopa; emylerumines and memylamelamines including alfretamine,triemylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimemylolomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (includingsynthetic analogue topotecan); bryostatin; callystatin; CC-1065(including its adozelesin, carzelesin and bizelesin syntheticanalogues); cryptophycins (articularly cryptophycin 1 and cryptophycin8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin;spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine,cholophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, foremustine, lomustine, nimustine,ranimustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, especially calicheamicin gammall and calicheamicin phiI1,see, e.g., Agnew, Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemicin,including dynemicin A; bisphosphonates, such as clodronate; anesperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromomophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, carrninomycin, carzinophilin, chromomycins, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin(including morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as demopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogues such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replinisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformthine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine;maytansinoids such as maytansine and ansamitocins; mitoguazone;mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin;losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid;2-ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-tricUorotriemylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethane; vindesine;dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman;gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta; taxoids,e.g., paclitaxel (TAXOL®, Bristol Meyers Squibb Oncology, Princeton,N.J.) and docetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France);chlorambucil; gemcitabine (Gemzar®); 6-thioguanine; mercaptopurine;methotrexate; platinum analogs such as cisplatin and carboplatin;vinblastine; platinum; etoposide (VP-16); ifosfamide; mitroxantrone;vancristine; vinorelbine (Navelbine®); novantrone; teniposide;edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11;topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO);retinoids such as retinoic acid; capecitabine; FOLFIRI (fluorouracil,leucovorin, and irinotecan) and pharmaceutically acceptable salts, acidsor derivatives of any of the above. One or more chemotherapeutic agentare used or included in the present application. For example,gemcitabine, nab-paclitaxel, and gemcitabine/nab-paclitaxel are usedwith the JAK inhibitor and/or PI3Kδ inhibitor for treatinghyperproliferative disorders.

Chemotherapeutic agents may also include, for example, anti-hormonalagents that act to regulate or inhibit hormone action on tumors such asanti-estrogens and selective estrogen receptor modulators (SERMs),including, for example, tamoxifen (including Nolvadex™), raloxifene,droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018,onapristone, and toremifene (Fareston®); inhibitors of the enzymearomatase, which regulates estrogen production in the adrenal glands,such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrolacetate (Megace®), exemestane, formestane, fadrozole, vorozole(Rivisor®), letrozole (Femara®), and anastrozole (Arimidex®.); andanti-androgens such as flutamide, nilutamide, bicalutamide, leuprohde,and goserelin; and pharmaceutically acceptable salts, acids orderivatives of any of the above.

The anti-angiogenic agents include, but are not limited to, retinoidacid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN®,ENDOSTATIN®, suramin, squalamine, tissue inhibitor ofmetalloproteinase-1, tissue inhibitor of metalloproternase-2,plasminogen activator inhibitor-1, plasminogen activator inbibitor-2,cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), plateletfactor 4, protamine sulphate (clupeine), sulphated chitin derivatives(prepared from queen crab shells), sulphated polysaccharidepeptidoglycan complex (sp-pg), staurosporine, modulators of matrixmetabolism, including for example, proline analogs((1-azetidine-2-carboxylic acid (LACA), cishydroxyproline,d,I-3,4-dehydroproline, thiaproline, .alpha.-dipyridyl,beta-aminopropionitrile fumarate,4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone; methotrexate, mitoxantrone,heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin,beta-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodiumthiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum,alpba-2-antiplasmin, bisantrene, lobenzarit disodium,n-2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”,thalidomide; angiostatic steroid, cargboxynaminolmidazole;metalloproteinase inhibitors such as BB94. Other anti-angiogenesisagents include antibodies, preferably monoclonal antibodies againstthese angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGFisoforms, VEGF-C, HGF/SF and Ang-1/Ang-2. See Ferrara N. and Alitalo, K.“Clinical application of angiogenic growth factors and their inhibitors”(1999) Nature Medicine 5:1359-1364.

The anti-fibrotic agents include, but are not limited to, the compoundssuch as beta-aminoproprionitrile (BAPN), as well as the compoundsdisclosed in U.S. Pat. No. 4,965,288 to Palfreyman, et al., issued Oct.23, 1990, entitled “Inhibitors of lysyl oxidase,” relating to inhibitorsof lysyl oxidase and their use in the treatment of diseases andconditions associated with the abnormal deposition of collagen; U.S.Pat. No. 4,997,854 to Kagan, et al., issued Mar. 5, 1991, entitled“Anti-fibrotic agents and methods for inhibiting the activity of lysyloxidase in situ using adjacently positioned diamine analogue substrate,”relating to compounds which inhibit LOX for the treatment of variouspathological fibrotic states, which are herein incorporated byreference. Further exemplary inhibitors are described in U.S. Pat. No.4,943,593 to Palfreyman, et al., issued Jul. 24, 1990, entitled“Inhibitors of lysyl oxidase,” relating to compounds such as2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine; as well as, e.g.,U.S. Pat. No. 5,021,456; U.S. Pat. No. 5,5059,714; U.S. Pat. No.5,120,764; U.S. Pat. No. 5,182,297; U.S. Pat. No. 5,252,608 (relating to2-(1-naphthyloxymemyl)-3-fluoroallylamine); and U.S. Patent ApplicationNo. 2004/0248871, which are herein incorporated by reference. Exemplaryanti-fibrotic agents also include the primary amines reacting with thecarbonyl group of the active site of the lysyl oxidases, and moreparticularly those which produce, after binding with the carbonyl, aproduct stabilized by resonance, such as the following primary amines:emylenemamine, hydrazine, phenylhydrazine, and their derivatives,semicarbazide, and urea derivatives, aminonitriles, such asbeta-aminopropionitrile (BAPN), or 2-nitroethylamine, unsaturated orsaturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine,2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamines,selenohomocysteine lactone. Also, the anti-fibrotic agents are copperchelating agents, penetrating or not penetrating the cells. Exemplarycompounds include indirect inhibitors such compounds blocking thealdehyde derivatives originating from the oxidative deamination of thelysyl and hydroxylysyl residues by the lysyl oxidases, such as thethiolamines, in particular D-penicillamine, or its analogues such as2-amino-5-mercapto-5-methylhexanoic acid,D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid,p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid,sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate,2-acetamidoethyl-2-acetamidoethanethiol sulphanate,sodium-4-mercaptobutanesulphinate trihydrate.

The immunotherapeutic agents include and are not limited to therapeuticantibodies suitable for treating patients; such as abagovomab,adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab,anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab,bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab,cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab,daratumumab, drozitumab, duligotumab, dusigitumab, detumomab,dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab,ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab, figitumumab,flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab,glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab,inotuzumab, intetumumab, ipilimumab, iratumumab, labetuzumab,lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab,matuzumab, milatuzumab, minretumomab, mitumomab, moxetumomab,narnatumab, naptumomab, necitumumab, nimotuzumab, nofetumomabn,ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab,oregovomab, panitumumab, parsatuzumab, patritumab, pemtumomab,pertuzumab, pintumomab, pritumumab, racotumomab, radretumab,rilotumumab, rituximab, robatumumab, satumomab, sibrotuzumab,siltuximab, simtuzumab, solitomab, tacatuzumab, taplitumomab,tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab,tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab,zalutumumab, CC49 and 3F8. The exemplified therapeutic antibodies may befurther labeled or combined with a radioisotope particle, such as indiumIn 111, yttrium Y 90, iodine 1-131.

The application also provides a method for treating a subject who isundergoing one or more standard therapies, such as chemotherapy,radiotherapy, immunotherapy, surgery, or combination thereof.Accordingly, one or more therapeutic agent or inhibitors may beadministered before, during, or after administration of chemotherapy,radiotherapy, immunotherapy, surgery or combination thereof.

In certain embodiments, the subject may be a human who is (i)substantially refractory to at least one chemotherapy treatment, or (ii)in relapse after treatment with chemotherapy, or both (i) and (ii). Insome of embodiments, the subject is refractory to at least two, at leastthree, or at least four chemotherapy treatments (including standard orexperimental chemotherapies).

In certain embodiments, the subject is refractory to at least one, atleast two, at least three, or at least four chemotherapy treatment(including standard or experimental chemotherapy) selected fromfludarabine, rituximab, obinutuzumab, alkylating agents, alemtuzumab andother chemotherapy treatments such as CHOP (cyclophosphamide,doxorubicin, vincristine, prednisone); R-CHOP (rituximab-CHOP);hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin,dexamethasone, methotrexate, cytarabine); R-hyperCVAD(rituximab-hyperCVAD); FCM (fludarabine, cyclophosphamide,mitoxantrone); R-FCM (rituximab, fludarabine, cyclophosphamide,mitoxantrone); bortezomib and rituximab; temsirolimus and rituximab;temsirolimus and Velcade®; Iodine-131 tositumomab (Bexxar®) and CHOP;CVP (cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP);ICE (iphosphamide, carboplatin, etoposide); R-ICE (rituximab-ICE); FCR(fludarabine, cyclophosphamide, rituximab); FR (fludarabine, rituximab);and D.T. PACE (dexamethasone, thalidomide, cisplatin, Adriamycin®,cyclophosphamide, etoposide).

Other examples of chemotherapy treatments (including standard orexperimental chemotherapies) are described below. In addition, treatmentof certain lymphomas is reviewed in Cheson, B. D., Leonard, J. P.,“Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma” The NewEngland Journal of Medicine 2008, 359(6), p. 613-626; and Wierda, W. G.,“Current and Investigational Therapies for Patients with CLL” Hematology2006, p. 285-294. Lymphoma incidence patterns in the United States isprofiled in Morton, L. M., et al. “Lymphoma Incidence Patterns by WHOSubtype in the United States, 1992-2001” Blood 2006, 107(1), p. 265-276.

Examples of immunotherapeutic agents treating lymphoma or leukemiainclude, but are not limited to, rituximab (such as Rituxan),alemtuzumab (such as Campath, MabCampath), anti-CD19 antibodies,anti-CD20 antibodies, anti-MN-14 antibodies, anti-TRAIL, Anti-TRAIL DR4and DR5 antibodies, anti-CD74 antibodies, apolizumab, bevacizumab,CHIR-12.12, epratuzumab (hLL2-anti-CD22 humanized antibody), galiximab,ha20, ibritumomab tiuxetan, lumiliximab, milatuzumab, ofatumumab,PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptidevaccine, tositumomab, autologous human tumor-derived HSPPC-96, andveltuzumab. Additional immunotherapy agents includes using cancervaccines based upon the genetic makeup of an individual patient's tumor,such as lymphoma vaccine example is GTOP-99 (MyVax®).

Examples of chemotherapy agents for treating lymphoma or leukemiainclude aldesleukin, alvocidib, antineoplaston AS2-1, antineoplastonA10, anti-thymocyte globulin, amifostine trihydrate, aminocamptothecin,arsenic trioxide, beta alethine, Bcl-2 family protein inhibitor ABT-263,BMS-345541, bortezomib (Velcade®), bryostatin 1, busulfan, carboplatin,campath-1H, CC-5103, carmustine, caspofungin acetate, clofarabine,cisplatin, Cladribine (Leustarin), Chlorambucil (Leukeran), Curcumin,cyclosporine, Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin),cytarabine, denileukin diftitox, dexamethasone, DT PACE, docetaxel,dolastatin 10, Doxorubicin (Adriamycin®, Adriblastine), doxorubicinhydrochloride, enzastaurin, epoetin alfa, etoposide, Everolimus(RAD001), fenretinide, filgrastim, melphalan, mesna, Flavopiridol,Fludarabine (Fludara), Geldanamycin (17-AAG), ifosfamide, irinotecanhydrochloride, ixabepilone, Lenalidomide (Revlimid®, CC-5013),lymphokine-activated killer cells, melphalan, methotrexate, mitoxantronehydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine,oblimersen (Genasense) Obatoclax (GX15-070), oblimersen, octreotideacetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991,PEGylated liposomal doxorubicin hydrochloride, pegfilgrastim, Pentstatin(Nipent), perifosine, Prednisolone, Prednisone, R-roscovitine(Selicilib, CYC202), recombinant interferon alfa, recombinantinterleukin-12, recombinant interleukin-11, recombinant flt3 ligand,recombinant human thrombopoietin, rituximab, sargramostim, sildenafilcitrate, simvastatin, sirolimus, Styryl sulphones, tacrolimus,tanespimycin, Temsirolimus (CC1-779), Thalidomide, therapeuticallogeneic lymphocytes, thiotepa, tipifarnib, Velcade® (bortezomib orPS-341), Vincristine (Oncovin), vincristine sulfate, vinorelbineditartrate, Vorinostat (SAHA), vorinostat, and FR (fludarabine,rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine,prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM(fludarabine, cyclophosphamide, mitoxantrone), FCR (fludarabine,cyclophosphamide, rituximab), hyperCVAD (hyperfractionatedcyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate,cytarabine), ICE (iphosphamide, carboplatin and etoposide), MCP(mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab plusCHOP), R-CVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE(rituximab-ICE), and R-MCP (R-MCP).

The therapeutic treatments can be supplemented or combined with any ofthe abovementioned therapies with stem cell transplantation ortreatment. One example of modified approach is radioimmunotherapy,wherein a monoclonal antibody is combined with a radioisotope particle,such as indium In 111, yttrium Y 90, iodine 1-131. Examples ofcombination therapies include, but are not limited to, Iodine-131tositumomab (Bexxar®), Yttrium-90 ibritumomab tiuxetan (Zevalin®),Bexxar® with CHOP.

Other therapeutic procedures include peripheral blood stem celltransplantation, autologous hematopoietic stem cell transplantation,autologous bone marrow transplantation, antibody therapy, biologicaltherapy, enzyme inhibitor therapy, total body irradiation, infusion ofstem cells, bone marrow ablation with stem cell support, invitro-treated peripheral blood stem cell transplantation, umbilical cordblood transplantation, immunoenzyme technique, pharmacological study,low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery,radiation therapy, and nonmyeloablative allogeneic hematopoietic stemcell transplantation.

Kits

Provided herein are also kits that include a compound of formula (I),(IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt,prodrug, or solvate thereof, and suitable packaging. In one embodiment,a kit further includes instructions for use. In one aspect, a kitincludes a compound of formula (I), (IA), (IB), (IC), or (II), or apharmaceutically acceptable salt, prodrug, or solvate thereof, and alabel and/or instructions for use of the compounds in the treatment ofthe indications, including the diseases or conditions, described herein.

Provided herein are also articles of manufacture that include a compoundof formula (I), (IA), (IB), (IC), or (II), or a pharmaceuticallyacceptable salt, prodrug, or solvate thereof, in a suitable container.The container may be a vial, jar, ampoule, preloaded syringe, andintravenous bag.

Pharmaceutical Compositions and Administration

Compounds provided herein are usually administered in the form ofpharmaceutical compositions. Thus, provides herein are alsopharmaceutical compositions that contain one or more of the compounds offormula (I), (IA), (IB), (IC), or (II), or a pharmaceutically acceptablesalt, prodrug, or solvate thereof, and one or more pharmaceuticallyacceptable vehicles selected from carriers, adjuvants and excipients.Suitable pharmaceutically acceptable vehicles may include, for example,inert solid diluents and fillers, diluents, including sterile aqueoussolution and various organic solvents, permeation enhancers,solubilizers and adjuvants. Such compositions are prepared in a mannerwell known in the pharmaceutical art. See, e.g., Remington'sPharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed.(1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S.Banker & C. T. Rhodes, Eds.).

The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical composition may be administered byvarious methods including, for example, rectal, buccal, intranasal andtransdermal routes. In certain embodiments, the pharmaceuticalcomposition may be administered by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant. In certainembodiments, the compound of formula (I), (IA), (IB), (IC), or (II), ora pharmaceutically acceptable salt, prodrug, or solvate thereof, isadministered intraveneously, intramuscularly, parenterally, nasally ororally.

One mode for administration is parenteral, for example, by injection.The forms in which the pharmaceutical compositions described herein maybe incorporated for administration by injection include, for example,aqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of thecompounds described herein. Administration may be via, for example,capsule or enteric coated tablets. In making the pharmaceuticalcompositions that include at least one compound of formula (I), (IA),(IB), (IC), or (II), or a pharmaceutically acceptable salt, prodrug, orsolvate thereof, the active ingredient is usually diluted by anexcipient and/or enclosed within such a carrier that can be in the formof a capsule, sachet, paper or other container. When the excipientserves as a diluent, it can be in the form of a solid, semi-solid, orliquid material, which acts as a vehicle, carrier or medium for theactive ingredient. Thus, the compositions can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, suspensions,emulsions, solutions, syrups, aerosols (as a solid or in a liquidmedium), ointments containing, for example, up to 10% by weight of theactive compound, soft and hard gelatin capsules, sterile injectablesolutions, and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions that include at least one compound of formula (I),(IA), (IB), (IC), or (II), or a pharmaceutically acceptable salt,prodrug, or solvate thereof, can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the subject by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods ofthe present invention employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds described herein in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may beconstructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of formula (I), (IA), (IB), (IC), or (II), or apharmaceutically acceptable salt, prodrug, or solvate thereof. Whenreferring to these preformulation compositions as homogeneous, theactive ingredient may be dispersed evenly throughout the composition sothat the composition may be readily subdivided into equally effectiveunit dosage forms such as tablets, pills and capsules.

Exemplary unit dosage levels of a compound of formula (I), (IA), (IB),(IC), or (II), or a pharmaceutically acceptable salt, prodrug, orsolvate thereof, for a human subject may, in certain variations, bebetween about 0.01 mg to about 1000 mg, between about 1 mg to about 15mg, or between about 50 mg to about 200 mg, or about 5 mg, about 10 mg,about 15 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about125 mg, or about 150 mg, or about 175 mg, about 200 mg, or about 250 mg.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can include an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation may include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect. In otherembodiments, compositions in pharmaceutically acceptable solvents may benebulized by use of inert gases. Nebulized solutions may be inhaleddirectly from the nebulizing device or the nebulizing device may beattached to a facemask tent, or intermittent positive pressure breathingmachine. Solution, suspension, or powder compositions may beadministered, preferably orally or nasally, from devices that deliverthe formulation in an appropriate manner.

Dosing

The specific dose level of a compound of formula (I), (IA), (IB), (IC),or (II), for any particular subject will depend upon a variety offactors including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,route of administration, and rate of excretion, drug combination and theseverity of the particular disease in the subject undergoing therapy.For example, a dosage may be expressed as a number of milligrams of acompound of formula (I), (IA), (IB), (IC), or (II) per kilogram of thesubject's body weight (mg/kg). Dosages of between about 0.1 and 150mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kgmay be appropriate. In other embodiments a dosage of between 0.5 and 60mg/kg may be appropriate. Normalizing according to the subject's bodyweight is particularly useful when adjusting dosages between subjects ofwidely disparate size, such as occurs when using the drug in bothchildren and adult humans or when converting an effective dosage in anon-human subject such as dog to a dosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compoundof formula (I), (IA), (IB), (IC), or (II) administered per dose or perday. Daily dosage of a compound of formula (I), (IA), (IB), (IC), or(II) may be between about 1 mg/day and 4,000 mg/day, between about 2,000mg/day to 4,000 mg/day, between about 1 mg/day to 2,000 mg/day, betweenabout 1 mg/day to 1,000 mg/day, between about 10 mg/day to 500 mg/day,between about 20 mg/day to 500 mg/day, between about 50 mg/day to 300mg/day, between about 75 mg/day to 200 mg/day, between about 15 mg/dayto 150 mg/day, or between 1 mg/day and 15 mg/day.

When administered orally, the total daily dosage for a human subject maybe between 1 mg and 1,000 mg, between about 10-500 mg/day, between about50-300 mg/day, between about 75-200 mg/day, or between about 100-150mg/day.

The compounds of formula (I), (IA), (IB), (IC), or (II) or thecompositions thereof may be administered once, twice, three, or fourtimes daily, using any suitable mode described above. Also,administration or treatment with the compounds formula (I), (IA), (IB),(IC), or (II) may be continued for a number of days; for example,commonly treatment would continue for at least 7 days, 14 days, or 28days, for one cycle of treatment. Treatment cycles are well known incancer chemotherapy, and are frequently alternated with resting periodsof about 1 to 28 days, commonly about 7 days or about 14 days, betweencycles. The treatment cycles, in other embodiments, may also becontinuous.

In a particular embodiment, the method comprises administering to thesubject an initial daily dose of about 1 to 500 mg of a compound offormula (I), (IA), (IB), (IC), or (II) and increasing the dose byincrements until clinical efficacy is achieved. Increments of about 5,10, 25, 50, or 100 mg can be used to increase the dose. The dosage canbe increased daily, every other day, twice per week, or once per week.

Synthesis of the Compounds of Formula (I), (IA), (IB), (IC) or (II)

The compounds of formula (I), (IA), (IB), (IC) or (II) may be preparedusing the methods disclosed herein and routine modifications thereof,which will be apparent given the disclosure herein and methods wellknown in the art. Conventional and well-known synthetic methods may beused in addition to the teachings herein. The synthesis of typicalcompounds described herein may be accomplished as described in thefollowing examples. If available, reagents may be purchasedcommercially, e.g., from Sigma Aldrich or other chemical suppliers.

General Synthesis

Typical embodiments of compounds described herein may be synthesizedusing the general reaction schemes described below. It will be apparentgiven the description herein that the general schemes may be altered bysubstitution of the starting materials with other materials havingsimilar structures to result in products that are correspondinglydifferent. Descriptions of syntheses follow to provide numerous examplesof how the starting materials may vary to provide correspondingproducts. Given a desired product for which the substituent groups aredefined, the necessary starting materials generally may be determined byinspection. Starting materials are typically obtained from commercialsources or synthesized using published methods. For synthesizingcompounds which are embodiments described in the present disclosure,inspection of the structure of the compound to be synthesized willprovide the identity of each substituent group. The identity of thefinal product will generally render apparent the identity of thenecessary starting materials by a simple process of inspection, giventhe examples herein.

Synthetic Reaction Parameters

The terms “solvent”, “inert organic solvent”, or “inert solvent” referto a solvent inert under the conditions of the reaction being describedin conjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, pyridine and the like). Unless specified to the contrary, thesolvents used in the reactions of the present invention are inertorganic solvents, and the reactions are carried out under an inert gas,preferably nitrogen.

The term “q.s.” means adding a quantity sufficient to achieve a statedfunction, e.g., to bring a solution to the desired volume (i.e., 100%).

Compounds of Formula I or II

One method of preparing compounds of formula (I) is shown in ReactionScheme I.

It should be understood that Reaction Scheme I depicted above anddescribed in further detail below may also be used to synthesizecompounds of formula (II).

Step 1—Preparation of a Compound of Formula (1)

The compound of formula (1) can be made by combining compounds (A), (B)and (C) in the presence of a dehydrating agent in a solvent. Compounds(A), (B) and (C) are commercially available. With respect to compound(A), R² is as defined herein. With respect to compound (B), R⁵ is asdefined herein. With respect to compound (C), R³ is as defined herein.Compound (A) can be mixed with Compound (B) in the presence of acoupling agent such as diphenyl phosphite in a solvent such as pyridine.After stirring at a temperature between ambient and 100° C. for between1 and 5 hours, compound (C) is added. After further stirring at atemperature between ambient and 100° C. for between 5 and 24 hours, thereaction mixture is allowed to cool to room temperature. To extract thecompound of formula (1), an organic solvent such as ethyl acetate(EtOAc) may be added, followed by washing with, mild acid, water, andbrine. The organic phase can be concentrated to obtain the compound offormula (1). The compound of formula (1) may be purified by any suitablemethods known in the art, such as chromatography on silica gel.Alternatively, the compound of formula (1) may be used in the next stepwithout purification.

Step 2—Preparation of a Compound of Formula (2)

The compound of formula (2) can be made by removing the protecting groupfrom the compound of formula (1). The compound of formula (1) isdissolved in a suitable solvent and treated with a suitable acid.Suitable solvents may include, for example, dichloromethane, dioxane, ormixtures thereof. Suitable acids may include, for example,trifluoroacetic acid or hydrochloric acid. The reaction can be carriedout temperatures between −20° C. to ambient temperature. On reactioncompletion, solvent is removed to obtain the compound of formula (2).

Step 3—Preparation of Compound (3)

Compound (3) can be made by performing a Sonogashira coupling ofcommercially available trimethylsilylalkyne (TMS-alkyne; compound (C))and 4-amino-6-chloro-5-iodopyrimidine (compound (D)). This type ofreaction generally uses a palladium catalyst, a copper catalyst and abase to form a carbon-carbon bond between the terminal alkyne ofcompound (C) and the heteroaryl halide (i.e., compound (D)). An exampleof a suitable palladium catalyst is Pd(PPh₃)₄. An example of a suitablecopper catalyst is CuI. An example of a suitable base is triethylamine(TEA). The coupling reaction may also be performed in the presence of asolvent. An example of a suitable solvent is N-methylpyrrolidone (NMP).The coupling reaction may be performed at elevated temperatures, forexample, between 80° C. and 100° C. for about 30 minutes to 24 hours.The reaction can be quenched by addition of water, and the reactionmixture can be extracted with a suitable solvent such as ethyl acetate(EtOAc). The organic layer can be isolated, dried (e.g., using Na₂SO₄),and concentrated. The residue can then be purified using any suitablemethods known in the art, for example, on a silica column, to yieldcompound (3). The residue may also be used crude, without purification,in the next step.

Step 4—Preparation of a Compound of Formula (4)

The compound of formula (4) can be made by a second Sonogashira couplingbetween compound (3) and compound (E) having the formula R¹—X, where R¹is as defined herein, and X is halo. The conditions for this secondSonogashira coupling is similar to the first coupling discussed above;however, this reaction further involves the use of a reagent to removethe TMS protecting group. Such a suitable reagent istetra-n-butylammonium fluoride (TBAF). Similar to the first Sonogashiracoupling, this reaction generally uses a palladium catalyst, a coppercatalyst and a base. An example of a suitable palladium catalyst isPd(PPh₃)₄. An example of a suitable copper catalyst is CuI. An exampleof a suitable base is triethylamine (TEA). The coupling reaction mayalso be performed in the presence of a solvent. An example of a suitablesolvent is N-methylpyrrolidone (NMP). This coupling reaction may beperformed at elevated temperatures, for example, between 80° C. to 100°C. for about 1 to 24 hours. The reaction is quenched by addition ofwater, and the reaction mixture can be extracted with a suitable solventsuch as ethyl acetate (EtOAc). The organic layer can be isolated, dried(e.g., using Na₂SO₄), and concentrated. The residue can then be purifiedusing any suitable methods known in the art, for example, on a silicacolumn, to yield a compound of formula (4). The residue may also be usedcrude, without purification, in the next step.

Step 5—Preparation of a Compound of Formula (I)

The compound of formula (I) can generally be prepared by couplingcompound of formula (2) and compound of formula (4) in the presence of asuitable base in a suitable solvent. An example of a suitable base isdiisopropylethylamine. An example of a suitable solvent isN-methylpyrrolidone (NMP). The reaction is typically performed at atemperature between 50° C. to 150° C. for about 30 minutes to 24 hours.Alternatively the reaction can be performed in a microwave at atemperature between 100° C. to 150° C. for about 30 minutes to 24 hours.Water can be added to quench the reaction upon completion, and theprecipitate may be filtered and then dissolved in an organic solventsuch as dichloromethane (DCM). The product can be isolated by methodsknown in the art, for example by removal of solvent under reducedpressure. The product can be purified using any suitable methods knownin the art, for example, chromatography of the residue on a silicacolumn.

Alternative Preparation

Another method of preparing compounds of formula (I) or (II) is shown inReaction Scheme II.

It should be understood that Reaction Scheme II depicted above anddescribed in further detail below may also be used to synthesizecompounds of formula (II).

The compound of formula (I) may also be prepared by coupling a compoundof formula (6) with commercially available compound of formula (G). Thecompound of formula (6) may be prepared in a manner similar to thatdescribed above for a compound of formula (1), by reacting a compound offormula (2) with an appropriately-substituted4-chloro-6-aminopyrimidine. Compound (G) has a structure of formulaR¹—C≡C, where R¹ is as defined herein.

The coupling reaction is performed in the presence of a palladiumcatalyst, a copper catalyst and a base to form a carbon-carbon bondbetween the terminal alkyne of Compound (G) and the compound of formula(6). An example of a suitable palladium catalyst is Pd(PPh₃)₂Cl₂. Anexample of a suitable copper catalyst is CuI. An example of a suitablebase is triethylamine (TEA). The coupling reaction may also be performedin the presence of a solvent. An example of a suitable solvent istetrahydrofuran (THF). The coupling reaction may be performed atelevated temperatures, for example, between 50° C. and 120° C. for about1 to 12 hours. Upon completion, the reaction is concentrated by removalof the solvent. The residue can be purified using any suitable methodsknown in the art, for example, chromatography of the residue on a silicacolumn.

Example 1a Preparation of a Compound of Formula (1)

A. Preparation of a Compound of Formula (1) in which n is 1, R² isChloro, and R³ is Phenyl

Diphenyl phosphonate (1.9 mL, 10 mmol) was added to a solution of2-amino-6-chlorobenzoic acid (495 mg, 2.9 mmol) and(S)-2-(tert-butoxycarbonylamino)propanoic acid (710 mg, 3.77 mmol) inpyridine (3 mL). The reaction mixture was stirred at 40° C. for 2 hours.Aniline (274 mg, 3.48 mmol) was then added to the reaction mixture,which was then stirred at 55° C. for 12 hours. The reaction mixture wascooled to room temperature. This mixture was then diluted with EtOAc (50mL), washed with 1N aqueous HCl (2×50 mL), brine (50 mL), and dried oversodium sulfate. The organics layer was filtered and concentrated invacuuo to afford material which was purified by column chromatography onSiO₂ eluting with EtOAc in hexanes (0-50%) to afford (S)-tert-butyl1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate asa solid. ES/MS m/z=400.1 (M+H)⁺.

B. Preparation of a Compound of Formula (1), Varying R² and R³

Following the procedure described in Example 1a.A and Reaction Scheme I,but varying the R² and R³ substituents, other compounds of formula (1)were prepared including:

-   (S)-tert-butyl    2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate,    ES/MS m/z=426.1 (M+H)⁺;-   (S)-tert-butyl    2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate,    ES/MS m/z=440.1 (M+H)⁺;-   (S)-tert-butyl    1-(8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate,    ES/MS m/z=384.1 (M+H)⁺;-   (S)-tert-butyl    1-(5,8-dichloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate,    ES/MS m/z=434.2 (M+H)⁺;-   (S)-tert-butyl    1-(5-chloro-8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate,    ES/MS m/z=418.1 (M+H)⁺;-   (S)-tert-butyl    1-(8-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate,    ES/MS m/z=400.1 (M+H)⁺;-   (S)-tert-butyl    1-(5,8-difluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate,    ES/MS m/z=402.1 (M+H)⁺;-   (S)-tert-butyl(1-(5-methoxy-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-chloro-8-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(8-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(3-(3-butylphenyl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(3-(3-t-butylphenyl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-chloro-3-(3-(methylsulfonyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(3-([1,1′-biphenyl]-3-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(3-(3-ethylphenyl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(8-fluoro-5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5,8-difluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-(difluoromethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-(difluoromethyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-(trifluoromethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-fluoro-8-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(3-(3-cyanophenyl)-5-(difluoromethyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(3-(3-cyanophenyl)-8-fluoro-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-(difluoromethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)carbamate;-   (S)-tert-butyl(1-(5-chloro-3-(3-methoxy-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-chloro-3-(3,5-difluorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (R)-tert-butyl(1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-chloro-3-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(6-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-chloro-3-(3-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(3-(3-cyanophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(3-(3-chlorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(3-(3-fluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)carbamate;-   (S)-tert-butyl(1-(3-(3,5-difluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)carbamate;-   (S)-tert-butyl(1-(3-(3-cyanophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-(methylsulfonyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-cyano-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-fluoro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-chloro-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-methyl-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(3-(5-fluoropyridin-3-yl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-chloro-3-morpholino-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-chloro-3-(3-(methyl    sulfonamidomethyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   tert-butyl((1S)-1-(5-chloro-3-((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(3-(azepan-1-yl)-5-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-chloro-4-oxo-3-(piperazin-1-yl)-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-methyl-3-(3-((N-methylmethylsulfonamido)methyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-chloro-3-(3-((N-methylmethylsulfonamido)methyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (S)-tert-butyl(1-(5-chloro-3-(3-((N-isobutylmethylsulfonamido)methyl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;-   (R)-tert-butyl(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-2-hydroxyethyl)carbamate;    and-   (R)-tert-butyl(1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methoxyethyl)carbamate.

Example 1b Preparation of a Compound of Formula (1)

A. Preparation of a Compound of Formula (1) in which n is 1, R² isCyano, and R³ is Phenyl

(S)-tert-butyl(1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate(500 mg, 1.13 mmol), zinc cyanide (166 mg, 1.41 mmol), andtetrakis(triphenylphosphine)Pd(0) (124 mg, 0.11 mmol) were combined inNMP (5 mL). The mixture was degassed under Ar and heated to 90° C.overnight. The reaction was poured into EtOAc, washed with water (3×),and purified by flash chromatography (40 g silica, 0-50% EtOAc/hexanes)to give(S)-tert-butyl(1-(5-cyano-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamateas a white solid. ES/MS 391.2 (M+H⁺).

Example 2a Preparation of a Compound of Formula (2)

A. Preparation of a Compound of Formula (2) in which n is 1, R² isChloro, and R³ is Phenyl

Trifluoroacetic acid (3 mL) was added to a solution of (S)-tert-butyl1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate (1g, 2.5 mmol) in dichloromethane (3 mL). The resultant was stirred atroom temperature for 3 hours. The solvent was removed in vacuuo toafford (S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one2,2,2-trifluoroacetic acid salt. ES/MS m/z=300.1 (M+H)⁺

B. Preparation of a Compound of Formula (2), Varying R² and R³

Following the procedure described in Example 2a.A and Reaction Scheme I,but varying the R² and R³ substituents, other compounds of formula (2)were prepared including:

-   (S)-5-chloro-3-phenyl-2-(pyrrolidin-2-yl)quinazolin-4(3H)-one, ES/MS    m/z=326.1 (M+H)⁺;-   (S)-5-chloro-3-phenyl-2-(piperidin-2-yl)quinazolin-4(3H)-one, ES/MS    m/z=340.1 (M+H)⁺;-   (S)-2-(1-aminoethyl)-5-(3-morpholino-3-oxopropyl)-3-phenylquinazolin-4(3H)-one,    ES/MS m/z=407.2 (M+H)⁺;-   (S)-3-(2-(1-aminoethyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-5-yl)-N,N-dimethylpropanamide,    ES/MS m/z=365.2 (M+H⁺);-   (S)-2-(1-aminoethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one, ES/MS    m/z=284.1 (M+H)⁺;-   (S)-2-(1-aminoethyl)-5,8-dichloro-3-phenylquinazolin-4(3H)-one,    ES/MS m/z=334.1 (M+H)⁺;-   (S)-2-(1-aminoethyl)-5-chloro-8-fluoro-3-phenylquinazolin-4(3H)-one,    ES/MS m/z=318.1 (M+H)⁺;-   (S)-2-(1-aminoethyl)-8-chloro-3-phenylquinazolin-4(3H)-one, ES/MS    m/z=300.1 (M+H)⁺;-   (S)-2-(1-aminoethyl)-5,8-difluoro-3-phenylquinazolin-4(3H)-one,    ES/MS m/z=302.1 (M+H)⁺;-   (S)-2-(1-aminoethyl)-5-chloro-8-methyl-3-phenylquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5-methyl-3-phenylquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile;-   (S)-2-(1-aminoethyl)-8-methyl-3-phenylquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-3-(3-butylphenyl)-5-chloroquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-3-(3-ethylphenyl)-5-chloroquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-3-(3-t-butylphenyl)-5-chloroquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5-chloro-3-(3-(methylsulfonyl)phenyl)quinazolin-4(3H)-one;-   (S)-3-([1,1′-biphenyl]-3-yl)-2-(1-aminoethyl)-5-chloroquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-8-fluoro-5-methyl-3-phenylquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5,8-difluoro-3-phenylquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5-(difluoromethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5-(difluoromethyl)-3-phenylquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5-(trifluoromethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5-fluoro-8-methyl-3-phenylquinazolin-4(3H)-one;-   (S)-3-(2-(1-aminoethyl)-5-(difluoromethyl)-4-oxoquinazolin-3    (4H)-yl)benzonitrile;-   (S)-3-(2-(1-aminoethyl)-8-fluoro-5-methyl-4-oxoquinazolin-3(4H)-yl)benzonitrile;-   (S)-2-(1-aminopropyl)-5-(difluoromethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5-chloro-3-(3-methoxy-2-methylphenyl)quinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5-chloro-3-(3,5-difluorophenyl)-8-fluoroquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one;-   (R)-2-(1-aminoethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5-chloro-3-(3-chlorophenyl)quinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one;-   (S)-3-(2-(1-aminoethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzonitrile;-   (S)-3-(2-(1-aminoethyl)-6-fluoro-4-oxoquinazolin-3(4H)-yl)benzonitrile;-   (S)-2-(1-aminoethyl)-3-(3-chlorophenyl)-6-fluoroquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5-fluoro-3-(3-fluorophenyl)quinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-3-(3-fluorophenyl)-5-methylquinazolin-4(3H)-one;-   (S)-2-(1-aminopropyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one;-   (S)-2-(1-aminopropyl)-3-(3,5-difluorophenyl)-5-methylquinazolin-4(3H)-one;-   (S)-3-(2-(1-aminoethyl)-5-fluoro-4-oxoquinazolin-3(4H)-yl)benzonitrile;-   (S)-2-(1-aminoethyl)-5-(methylsulfonyl)-3-phenylquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile;-   (S)-2-(1-aminoethyl)-5-fluoro-3-(pyridin-3-yl)quinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5-chloro-3-(pyridin-3-yl)quinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5-methyl-3-(pyridin-3-yl)quinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-3-(5-fluoropyridin-3-yl)-5-methylquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5-chloro-3-morpholinoquinazolin-4(3H)-one;-   (S)—N-(3-(2-(1-aminoethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzyl)methanesulfonamide;-   (S)-1-aminoethyl)-5-chloro-3-((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)quinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-3-(azepan-1-yl)-5-chloroquinazolin-4(3H)-one;-   (S)-2-(1-aminoethyl)-5-chloro-3-(piperazin-1-yl)quinazolin-4(3H)-one;-   (S)—N-(3-(2-(1-aminoethyl)-5-methyl-4-oxoquinazolin-3    (4H)-yl)benzyl)-N-methylmethanesulfonamide;-   (S)—N-(3-(2-(1-aminoethyl)-5-chloro-4-oxoquinazolin-3    (4H)-yl)benzyl)-N-methylmethanesulfonamide;-   (S)—N-(3-(2-(1-aminoethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzyl)-N-isobutylmethanesulfonamide;-   (R)-2-(1-amino-2-hydroxyethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;    and-   (R)-2-(1-amino-2-methoxyethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one.

Example 2b Preparation of a Compound of Formula (2)

A. Preparation of a Compound of Formula (2) in which n is 1, R² isHydroxy, and R³ is Phenyl

To a solution of(S)-tert-butyl(1-(5-methoxy-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate(100 mg, 0.25 mmol) in DCM (3 mL) at −78° C. was added BBr₃ (1M/DCM,0.63 mL, 0.63 mmol). The reaction was stirred at −78° C. for 20 min,then warmed to ambient temperature. After stirring 10 minutes at ambienttemperature, MeOH (5 mL) was added. The reaction was concentrated invacuo. Purification by flash chromatography (12 g silica, 0-100%EtOAc/DCM then 0-30% MeOH/DCM) provided(S)-2-(1-aminoethyl)-5-hydroxy-3-phenylquinazolin-4(3H)-on as an orangeresidue. ES/MS 282.1 (M+H⁺).

Example 3 Preparation of a Compound of Formula (3)

To 4-amino-6-chloro-5-iodopyrimidine (2.0 g, 7.8 mmol) in NMP (20 mL)was added Pd(PPh₃)₄ (0.907 g, 0.785 mmol), CuI (0.149 g, 0.785 mmol),TEA (2.20 ml, 15.7 mmol), and TMS-alkyne (1.22 mL, 8.64 mmol). Afterstirring at 90° C. for 1 hour, water was added and the mixture wasextracted with EtOAc (3×50 mL), dried (Na₂SO₄), and concentrated. Theresidue was purified on a silica column (0-75% ethyl acetate in hexanes)to give 6-chloro-5-((trimethylsilyl)ethynyl)pyrimidin-4-amine. ES/MSm/z=226.1 (M⁺), 228.1(M⁺²).

Example 4 Preparation of a Compound of Formula (4)

A. Preparation of a Compound of Formula (4) in which R¹ is5-Methoxycarbonylpyridin-2-yl

To 6-chloro-5-((trimethylsilyl)ethynyl)pyrimidin-4-amine (30.0 mg, 1.33mmol) (prepared according to the procedure in Example 3 above) in NMP (5mL) was added Pd(PPh₃)₄ ₍0.154 g, 0.133 mmol), CuI (25 mg, 0.78 mmol),TEA (0.371 mL, 2.66 mmol), tBAF (0.385 mL, 2.66 mmol), and methyl6-bromonicotinate (0.345 g 1.60 mmol). After stirring at 90° C.overnight, water was added and the mixture was extracted with EtOAc(3×25 mL), dried (Na₂SO₄), and concentrated. Methyl6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)nicotinate was carriedforward crude. ES/MS m/z=289.1 (M⁺), 291.0 (M⁺²).

B. Preparation of a Compound of Formula (4), Varying R¹

Following the procedure described in Example 4A and Reaction Scheme I,but varying the R¹ substituent, other compounds of formula (4) wereprepared including:

-   6-chloro-5-(pyridin-2-ylethynyl)pyrimidin-4-amine, ES/MS m/z=231.5    (M+H⁺);-   5-((1H-pyrazol-4-yl)ethynyl)-6-chloropyrimidin-4-amine, ES/MS    m/z=220 (M+H⁺);-   6-chloro-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-amine, ES/MS    m/z=249.5 (M+H⁺);-   6-chloro-5-((3-fluoro-5-methoxyphenyl)ethynyl)pyrimidin-4-amine,    ES/MS m/z=278.2 (M+H⁺);-   6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)benzo[d]thiazol-2-amine,    ES/MS m/z=302.5 (M+H⁺);-   6-chloro-5-(pyridin-2-ylethynyl)pyrimidin-4-amine, ES/MS m/z=231.2    (M+H⁺);-   6-chloro-5-(pyridin-3-ylethynyl)pyrimidin-4-amine, ES/MS m/z=231.1    (M+H⁺);-   6-chloro-5-(pyrimidin-5-ylethynyl)pyrimidin-4-amine, ES/MS m/z=232.6    (M+H⁺);-   5-((5-aminopyridin-2-yl)ethynyl)-6-chloropyrimidin-4-amine, ES/MS    m/z=246.7 (M+H⁺);-   5-((4-amino-6-chloropyrimidin-5-yl)ethynyl)pyrimidin-2-amine, ES/MS    m/z=247 (M+H⁺);-   5-((6-aminopyridin-2-yl)ethynyl)-6-chloropyrimidin-4-amine, ES/MS    m/z=246.1 (M+H⁺);-   4-(4-amino-6-chloropyrimidin-5-yl)-2-methylbut-3-yn-2-ol, ES/MS    m/z=212.3 (M+H⁺);-   6-chloro-5-((4-(trifluoromethoxy)phenyl)ethynyl)pyrimidin-4-amine,    ES/MS m/z=314.5 (M+H⁺);-   6-chloro-5-(cyclopropylethynyl)pyrimidin-4-amine, ES/MS m/z=194    (M+H⁺);-   (S)-4-(4-amino-6-chloropyrimidin-5-yl)but-3-yn-2-ol, ES/MS m/z=198.1    (M+H⁺);-   (R)-4-(4-amino-6-chloropyrimidin-5-yl)but-3-yn-2-ol, ES/MS m/z=198.2    (M+H⁺);-   5-((6-amino-4-(trifluoromethyl)pyridin-3-yl)ethynyl)-6-chloropyrimidin-4    amine, ES/MS m/z=314.7 (M+H⁺);-   6-chloro-5-(pyrazin-2-ylethynyl)pyrimidin-4-amine, ES/MS m/z=232.5    (M+H⁺);-   6-chloro-5-(pyridazin-3-ylethynyl)pyrimidin-4-amine, ES/MS m/z=232.2    (M+H⁺);-   6-chloro-5-((3-fluoro-5-methoxyphenyl)ethynyl)pyrimidin-4-amine;-   6-chloro-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidine-2,4-diamine;-   6-chloro-5-((3-fluoropyridin-2-yl)ethynyl)pyrimidin-4-amine;-   6-chloro-5-((3-methoxypyridin-2-yl)ethynyl)pyrimidin-4-amine;-   6-chloro-5-((3,5-difluoropyridin-2-yl)ethynyl)pyrimidin-4-amine;-   6-chloro-5-(pyrazin-2-ylethynyl)pyrimidin-4-amine;-   6-chloro-5-(pyrimidin-2-ylethynyl)pyrimidin-4-amine;-   6-chloro-5-((5-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-amine;-   6-chloro-5-((5-methylpyridin-2-yl)ethynyl)pyrimidin-4-amine;-   6-chloro-5-((5-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-amine;-   6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)nicotinamide;-   isopropyl 6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)nicotinate;-   6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)nicotinic acid;-   6-chloro-5-((5-fluoro-6-methylpyridin-2-yl)ethynyl)pyrimidin-4-amine;-   6-chloro-5-((6-methylpyridin-2-yl)ethynyl)pyrimidin-4-amine;-   6-chloro-5-((3-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-amine;-   6-chloro-5-((3-methylpyridin-2-yl)ethynyl)pyrimidin-4-amine;-   6-chloro-5-(cyclopentylethynyl)pyrimidin-4-amine;-   6-chloro-5-(cyclohexylethynyl)pyrimidin-4-amine;-   6-chloro-5-((4-methylpyridin-2-yl)ethynyl)pyrimidin-4-amine;-   6-chloro-5-((4-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-amine;-   6-chloro-5-((4-(difluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-amine;-   6-chloro-5-((4-ethylpyridin-2-yl)ethynyl)pyrimidin-4-amine;-   6-chloro-5-((6-methylpyridin-2-yl)ethynyl)pyrimidin-4-amine;-   1-(2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)pyridin-3-yl)ethanone;-   1-(2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)pyridin-6-yl)ethanone;-   (2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)pyridin-4-yl)methanol;-   (2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)pyridin-6-yl)methanol;-   2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)isonicotinamide;-   1-(6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)pyridin-2-yl)ethanol;-   methyl 2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)isonicotinate;-   5-((6-(aminomethyl)pyridin-2-yl)ethynyl)-6-chloropyrimidin-4-amine;-   2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)isonicotinic acid;-   1-(3-((4-amino-6-chloropyrimidin-5-yl)ethynyl)phenyl)ethanone;-   (3-((4-amino-6-chloropyrimidin-5-yl)ethynyl)phenyl)methanol; and-   (2-((4-amino-6-chloropyrimidin-5-yl)ethynyl)pyridin-3-yl)methanol.

Example 5 Preparation of a Compound of Formula (6)

A. Preparation of a Compound of Formula (6) in which n is 1, R² isChloro, and R³ is Phenyl

To (S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (400 mg,1.33 mmol) (prepared according to the procedure in Example 2a.A above)and 4-amino-6-chloro-5-iodopyrimidine (338 mg, 1.32 mmol) in IPA (5 mL)was added Hunig's base (0.4 mL). After stirring at 90° C. for 2 hours ina microwave reactor, water was added and the mixture was extracted withEtOAc (3×50 mL), dried (MgSO₄), and concentrated. The residue waspurified on a reverse phase system run from 0 to 95% ACN in water (0.1%TFA) to give(S)-2-(1-(6-amino-5-iodopyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one.ES/MS m/z=519.0 (M⁺), 521.0(M⁺²).

Example 6 Preparation of a Compound of Formula (I) or (II)

A. Preparation of a Compound of Formula (I) in which n is 1, R¹ is5-Methoxycarbonylpyridin-2-yl, R² is Chloro, and R³ is Phenyl (Compound3a)

To methyl 6-((4-amino-6-chloropyrimidin-5-yl)ethynyl)nicotinate (50 mg,0.17 mmol) (prepared according to the procedure in Example 3 above) inNMP (5 mL) was added(S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (62 mg 0.21mmol) (prepared according to the procedure in Example 2A above), KF (33mg 0.35 mmol), and Hunig's base (0.15 ml, 0.21 mmol). After stirringovernight at 120° C. the reaction was cooled to rt. Water was added. Theprecipitate was filtered, and then dissolved in DCM. Purification onsilica with 0 to 100% EtOAc in hexanes then 0 to 20% MeOH in EtOAc gavematerial that required further purification. Purification on a reversephase system run from 0 to 95% ACN in water (0.1% TFA) gave (S)-methyl6-((4-amino-6-(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidin-5-yl)ethynyl)nicotinate.

B. Preparation of a Compound of Formula (I) in which n is 1, R² isChloro, and R¹ and R³ are Both Phenyl (Compound 51a)

To(S)-2-(1-(6-amino-5-iodopyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(58 mg, 0.11 mmol) (prepared according to the procedure in Example 5A)in THF (5 mL) was added Pd(PPh₃)₂Cl₂ (2 mg, 2.5%), CuI (1 mg, 5%), TEA(0.1 mL, 0.16 mmol), and phenylacetylene (20 mg 0.16 mmol). Afterstirring at 70° C. for 2 hours, the solvent was stripped. The residuewas purified on silica with 0 to 10% MeOH in DCM to give material thatrequired further purification. Purification on silica with 0 to 100%EtOAc in hexanes gave(S)-2-(1-(6-amino-5-(phenylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one.¹H NMR (400 MHz, DMSO-D₆) δ 7.88 (s, 1H), 7.78 (t, J=8.0 Hz, 1H), 7.88(dt, J=6.8, 1.6 Hz, 2H), 7.59-7.41 (m, 10H), 6.92 (d, J=7.0 Hz, 1H),6.75 (bs, 2H), 4.73 (p, J=6.8 Hz, 1H), 1.35 (d, J=6.7 Hz, 3H). ES/MSm/z=493.1 (M+H⁺).

C. Preparation of a Compound of Formula (I) or (II), Varying R¹, R² andR³

Following the procedure described in Examples 6A and 6B, and ReactionScheme I, but varying the R¹ substituent, other compounds of formula (I)or (II) were prepared including:

(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5,8-difluoro-3-phenylquinazolin-4(3H)-one(Compound 4a); ¹H NMR (400 MHz, DMSO-d6) δ 8.64 (d, 1H, J=2.3 Hz), 8.02(s, 1H), 7.91-7.82 (m, 2H), 7.80-7.74 (m, 1H), 7.60-7.45 (m, 5H),7.39-7.31 (m, 3H), 4.91-4.82 (m, 2H), 1.40 (d, 3H, J=6.6 Hz); ES/MSm/z=514.1 (M+H)⁺;

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-5,8-difluoroquinazolin-4(3H)-one(Compound 1a); ¹H NMR (400 MHz, DMSO-d6) δ 8.81-8.39 (m, 1H), 8.06 (s,1H), 7.95-7.71 (m, 2H), 7.64-7.37 (m, 3H), 7.42-7.08 (m, 3H), 5.01 (t,J=6.9 Hz, 1H), 1.45 (d, J=6.6 Hz, 3H). ES/MS 550.3(M+H+);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-8-fluoroquinazolin-4(3H)-one(Compound 2a); ¹H NMR (400 MHz, DMSO-d6) δ 8.76-8.44 (m, 1H), 8.05 (s,1H), 7.98-7.64 (m, 3H), 7.64-7.39 (m, 3H), 7.39-7.13 (m, 2H), 5.19-4.89(m, 1H), 1.70-1.32 (m, 3H). ES/MS 532.2(M+H+);

(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-8-chloro-3-phenylquinazolin-4(3H)-one(Compound 5a); ¹H NMR (400 MHz, DMSO-d6) δ 8.65 (d, 1H, J=2.8 Hz), 8.09(s, 1H), 8.07 (s, 1H), 7.99 (d, 1H, J=7.8 Hz), 7.92-7.84 (m, 2H),7.68-7.47 (m, 8H), 5.09-5.01 (m, 2H), 1.38 (d, 3H, J=6.7 Hz); ES/MSm/z=512.1 (M+H)⁺;

(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-8-fluoro-3-phenylquinazolin-4(3H)-one(Compound 6a); ¹H NMR (400 MHz, DMSO-d6) δ 8.65 (d, 1H, J=2.7 Hz), 8.06(s, 1H), 7.91-7.83 (m, 2H), 7.73 (dt, 1H, J=9.0 and 0.8 Hz), 7.65-7.44(m, 8H), 4.91-4.84 (m, 2H), 1.40 (d, 3H, J=6.7 Hz); ES/MS m/z=530.1(M+H)⁺;

(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one(Compound 7a); ¹H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J=14.3 Hz, 1H), 8.05(s, 1H), 7.88 (dtd, J=10.9, 8.5, 4.5 Hz, 2H), 7.65 (d, J=8.2 Hz, 1H),7.57-6.98 (m, 8H), 5.00-4.69 (m, 1H), 1.33 (d, J=6.6 Hz, 3H). ES/MSm/z=532.2 (M+H⁺);

(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(Compound 8a); ¹H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J=2.9 Hz, 1H),8.01-7.79 (m, 4H), 7.73-7.39 (m, 8H), 7.38-7.17 (m, 2H), 4.85-4.74 (m,1H), 1.35 (dd, J=13.1, 6.6 Hz, 3H). ES/MS m/z=496.1 (M+H⁺);

(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 9a); ¹H NMR (400 MHz, dmso) δ 8.68 (d, J=2.4 Hz, 1H), 8.01 (s,1H), 7.97-7.73 (m, 4H), 7.60 (d, J=7.7 Hz, 1H), 7.53 (d, J=8.7 Hz, 2H),7.38 (m, 8.9 Hz, 4H), 4.97-4.80 (m, 1H), 1.38 (d, J=6.5 Hz, 3H). ES/MSm/z=548.3 (M+H⁺);

(S)-2-(1-(6-amino-5-((5-methoxypyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5,8-dichloro-3-phenylquinazolin-4(3H)-one(Compound 10a); ¹H NMR (400 MHz, DMSO-d6) δ 8.34 (d, 1H, J=3.1 Hz), 8.04(s, 1H), 7.93 (d, 1H, J=8.6 Hz), 7.76 (d, 1H, J=8.6 Hz), 7.60-7.48 (m,8H), 7.45-7.32 (br s, 2H), 5.04-4.97 (m, 2H), 1.35 (d, 3H, J=6.6 Hz);ES/MS m/z=558.2 (M+H)⁺;

(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5,8-dichloro-3-phenylquinazolin-4(3H)-one(Compound 11a); ¹H NMR (400 MHz, DMSO-d6) δ 8.65 (d, 1H, J=3.1 Hz), 8.04(s, 1H), 7.94 (d, 1H, J=8.6 Hz), 7.91-7.84 (m, 2H), 7.60-7.49 (m, 8H),5.04-4.97 (m, 2H), 1.36 (d, 3H, J=6.7 Hz); ES/MS m/z=546.1 (M+H)⁺;

(S)-2-(1-(6-amino-5-((5-methoxypyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one(Compound 12a); ¹H NMR (400 MHz, DMSO-d6) δ 8.35 (d, 1H, J=3.5 Hz), 8.08(s, 1H), 7.95 (dm, 1H, J=7.8 Hz), 7.77 (d, 1H, J=8.6 Hz), 7.76-7.67 (m,2H), 7.60-7.47 (m, 8H), 4.96-4.89 (m, 2H), 1.43 (d, 3H, J=7.1 Hz); ES/MSm/z=508.2 (M+H)⁺;

(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one(Compound 13a); ¹H NMR (400 MHz, DMSO-d6) δ 8.57 (d, 1H, J=2.8 Hz), 7.99(s, 1H), 7.88 (d, 1H, J=7.8 Hz), 7.84-7.76 (m, 2H), 7.70-7.50 (m, 2H),7.54-7.35 (m, 6H), 4.89-4.82 (m, 2H), 1.35 (d, 3H, J=6.6 Hz); ES/MSfound m/z=496.2 (M+H)⁺;

(S)-2-(1-(6-amino-5-(pyridazin-3-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 14a); ¹H NMR (400 MHz, dmso) δ 13.07-12.79 (m, 1H), 9.15 (s,1H), 8.93-8.52 (m, 1H), 8.37-7.97 (m, 2H), 8.01-7.47 (m, 8H), 7.40 (s,2H), 4.81 (s, 1H), 1.49 (d, J=6.8 Hz, 3H). ES/MS m/z=495.2 (M+H⁺);

(S)-2-(1-(6-amino-5-((6-aminopyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 15a); ¹H NMR (400 MHz, dmso) δ 7.97 (s, 2H), 7.87 (s, 1H),7.81-7.69 (m, 1H), 7.67-7.55 (m, 2H), 7.51 (d, J=9.7 Hz, 1H), 7.39 (m,2H), 7.27 (d, J=10.2 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H), 6.87 (d, J=8.5 Hz,1H), 4.85 (s, 1H), 1.46 (d, J=6.4 Hz, 3H). ES/MS m/z=545.9 (M+H⁺);

(S)-2-(1-(6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 16a); ¹H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J=1.6 Hz, 1H), 8.78(dd, J=2.5, 1.6 Hz, 1H), 8.60 (d, J=24.1 Hz, 1H), 8.07 (s, 1H),7.92-7.68 (m, 2H), 7.64-7.23 (m, 9H), 4.89-4.61 (m, 1H), 1.34 (d, J=6.7Hz, 3H). ES/MS m/z=495.4 (M+H⁺);

(S)-2-(1-(6-amino-5-((6-amino-4-(trifluoromethyl)pyridin-3-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 17a); ¹H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=47.4 Hz, 1H),8.11 (s, 1H), 7.76 (t, J=8.0 Hz, 1H), 7.68-7.34 (m, 6H), 7.32-7.13 (m,2H), 7.10 (s, 3H), 6.81 (s, 1H), 4.96 (d, J=6.2 Hz, 1H), 1.41 (d, J=6.5Hz, 3H). ES/MS m/z=613.7 (M+H⁺);

(S)-2-(1-(6-amino-5-((6-amino-4-(trifluoromethyl)pyridin-3-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 18a); ¹H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.09 (s, 1H),7.86-7.60 (m, 1H), 7.63-7.37 (m, 8H), 7.04 (s, 4H), 6.83 (d, J=12.2 Hz,1H), 5.02-4.52 (m, 1H), 1.35 (d, J=6.7 Hz, 3H). ES/MS m/z=577.5 (M+H⁺);

2-((S)-1-(6-amino-5-((R)-3-hydroxybut-1-ynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 19a); ¹H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.83-7.71 (m,1H), 7.66 (d, J=7.0 Hz, 1H), 7.55 (dd, J=16.0, 14.0 Hz, 10H), 4.84-4.48(m, 2H), 1.52-1.38 (m, 3H), 1.33 (d, J=6.6 Hz, 3H). ES/MS m/z=461(M+H⁺);

2-((S)-1-(6-amino-5-((S)-3-hydroxybut-1-ynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 19b); ¹H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.83-7.69 (m,1H), 7.67 (dd, J=8.2, 1.1 Hz, 1H), 7.57-7.43 (m, 8H), 7.38-7.07 (m, 2H),4.89-4.55 (m, 2H), 1.45 (d, J=6.6 Hz, 3H), 1.32 (d, J=6.7 Hz, 3H). ES/MSm/z=461.9(M+H⁺);

2-((S)-1-(6-amino-5-((R)-3-hydroxybut-1-ynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 20a); ¹H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.79 (t, J=8.1Hz, 5H), 7.67 (d, J=8.3 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.52 (d, J=8.1Hz, 1H), 7.44-7.17 (m, 6H), 4.85 (s, 1H), 4.67 (d, J=6.6 Hz, 1H), 1.41(dd, J=6.6, 6.6 Hz, 6H). ES/MS m/z=497.1(M+H⁺);

2-((S)-1-(6-amino-5-((S)-3-hydroxybut-1-ynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 20b); ¹H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.80 (t, J=8.0Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.52 (d, J=9.1Hz, 1H), 7.46-7.10 (m, 6H), 4.85 (s, 1H), 4.66 (d, J=6.6 Hz, 1H),1.51-1.34 (m, 6H). ES/MS m/z=497.3(M+H⁺);

(S)-2-(1-(6-amino-5-(cyclopropylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 23a); ¹H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.81 (t, J=8.2Hz, 2H), 7.80 (d, J=8.1 Hz, 2H), 7.62 (dd, J=7.7, 7.9 Hz, 1H), 7.51 (d,J=9.0 Hz, 1H), 7.37 (d, J=9.4 Hz, 1H), 7.27 (d, J=9.2 Hz, 1H), 7.21-7.06(m, 1H), 4.84 (s, 1H), 1.64 (s, 1H), 1.38 (d, J=6.6 Hz, 3H), 1.01-0.73(m, 4H). ES/MS m/z=494.5(M+H⁺);

(S)-2-(1-(6-amino-5-(cyclopropylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 24a); ¹H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.80 (t, J=8.0Hz, 1H), 7.63 (dd, J=8.2, 1.2 Hz, 1H), 7.59 (dd, J=7.8, 1.1 Hz, 1H),7.56-7.54 (m, 2H), 7.49 (dd, J=4.5, 3.1 Hz, 4H), 7.34 (s, 2H), 4.83-4.66(m, 1H), 1.69 (ddd, J=13.1, 8.2, 5.1 Hz, 1H), 1.33 (d, J=6.7 Hz, 3H),1.05-0.73 (m, 4H). ES/MS m/z=457.2(M+H⁺);

(S)-2-(1-(6-amino-5-((4-(trifluoromethoxy)phenyl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 26a); ¹H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.87-7.81 (m,2H), 7.78 (t, J=8.0 Hz, 1H), 7.60 (dd, J=12.2, 4.5 Hz, 3H), 7.52 (d,J=9.1 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.36 (t, J=9.3 Hz, 2H), 7.29 (d,J=9.2 Hz, 1H), 5.00-4.81 (m, 1H), 1.45 (d, J=6.7 Hz, 3H). ES/MSm/z=613.9(M+H⁺);

(S)-2-(1-(6-amino-5-((4-(trifluoromethoxy)phenyl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 27a); ¹H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.89-7.80 (m,1H), 7.80-7.64 (m, 1H), 7.64-7.26 (m, 13H), 4.88-4.64 (m, 1H), 1.38 (d,J=6.7 Hz, 3H). ES/MS m/z=577.2(M+H⁺);

(S)-2-(1-(6-amino-5-(3-hydroxy-3-methylbut-1-ynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 28a); ¹H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.84-7.75 (m,2H), 7.67 (dd, J=8.2, 1.2 Hz, 1H), 7.60 (dd, J=7.8, 1.2 Hz, 1H), 7.54(d, J=8.8 Hz, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.35 (d, J=9.1 Hz, 1H), 7.10(s, 2H), 4.85 (s, 1H), 1.52 (d, J=3.8 Hz, 6H), 1.38 (d, J=6.7 Hz, 3H).ES/MS m/z=511.9(M+H⁺);

(S)-2-(1-(6-amino-5-(3-hydroxy-3-methylbut-1-ynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 29a); ¹H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.79 (t, J=8.0Hz, 1H), 7.71-7.63 (m, 1H), 7.60-7.46 (m, 8H), 7.30 (s, 2H), 4.89-4.61(m, 1H), 1.54 (d, J=4.0 Hz, 6H), 1.32 (d, J=6.6 Hz, 3H). ES/MSm/z=475.9(M+H⁺);

(S)-2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-methyl-3-phenylquinazolin-4(3H)-one(Compound 30a); ¹H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.33-8.20 (m,1H), 8.04 (s, 1H), 7.94-7.83 (m, 1H), 7.80-7.64 (m, 2H), 7.46 (dd,J=64.5, 30.9 Hz, 10H), 4.79 (s, 1H), 2.79-2.53 (m, 3H), 1.29 (dd,J=24.6, 6.7 Hz, 5H). ES/MS m/z=474.5(M+H⁺);

(S)-2-(1-(6-amino-5-((6-aminopyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 31a); ¹H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.88 (s, 1H),7.76 (t, J=8.0 Hz, 1H), 7.55 (m, 9H), 7.23 (d, J=7.7 Hz, 2H), 6.88 (d,J=8.9 Hz, 1H), 4.84-4.53 (m, 1H), 1.42 (d, J=6.8 Hz, 3H). ES/MSm/z=509.3(M+H⁺);

(S)-2-(1-(6-amino-5-((2-aminopyrimidin-5-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 32a); ¹H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 2H), 8.16 (s, 1H),7.81 (dd, J=22.0, 13.9 Hz, 1H), 7.72-7.47 (m, 7H), 7.39 (s, 1H), 7.32(d, J=8.9 Hz, 1H), 7.21 (s, 1H), 4.95 (s, 1H), 1.48 (d, J=6.7 Hz, 3H).ES/MS m/z=546.5(M+H⁺);

(S)-2-(1-(6-amino-5-((2-aminopyrimidin-5-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 33a); ¹H NMR (400 MHz, DMSO-d6) δ 8.68-8.47 (m, 2H), 8.16 (s,1H), 7.91 (d, J=26.6 Hz, 1H), 7.77 (t, J=8.0 Hz, 2H), 7.62-7.39 (m, 8H),7.24 (s, 2H), 4.92-4.73 (m, 1H), 1.43 (d, J=6.8 Hz, 3H). ES/MSm/z=510.1(M+H⁺);

(S)-2-(1-(6-amino-5-((5-aminopyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 34a); ¹H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.06 (s, 1H),8.03 (d, J=2.6 Hz, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.83-7.77 (m, 1H), 7.71(dd, J=14.0, 9.7 Hz, 3H), 7.62 (d, J=7.7 Hz, 2H), 7.55 (d, J=8.2 Hz,2H), 7.46-7.37 (m, 2H), 7.33 (d, J=9.0 Hz, 2H), 7.27 (m, 1H), 4.95-4.89(m, 1H), 1.45 (d, J=6.6 Hz, 3H). ES/MS m/z=545.9(M+H⁺);

(S)-2-(1-(6-amino-5-((5-aminopyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 35a); ¹H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J=12.3 Hz, 2H),7.84-7.67 (m, 4H), 7.67-7.47 (m, 6H), 7.25 (s, 1H), 4.93-4.62 (m, 1H),1.35 (dd, J=42.9, 6.8 Hz, 3H). ES/MS m/z=508.3(M+H⁺);

(S)-2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)piperidin-2-yl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 36a); ¹H NMR (400 MHz, DMSO-D₆) δ 8.61 (d, J=5.5 Hz, 1H), 8.08(s, 1H), 7.88 (t, J=9.5 Hz, 1H), 7.78-7.38 (m, 10H), 5.15 (m, 1H), 4.72(m, 1H), 4.09 (m, 1H), 2.16-1.41 (m, 8H); ES/MS m/z=534.1 (M+H)⁺;

(S)-2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)pyrrolidin-2-yl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 37a); ¹H NMR (400 MHz, DMSO-D₆) δ 8.63 (m, 1H), 8.23 (d,J=14.2 Hz, 1H), 7.97-7.39 (m, 11H), 4.64 (m, 1H), 4.41 (m, 1H), 4.25 (m,1H), 2.37-2.09 (m, 4H), 1.94 (m, 2H); ES/MS m/z=520.1 (M+H)⁺;

(S)-3-(2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzamide(Compound 38a); ¹H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J=4.9 Hz, 1H), 8.13(d, J=11.7 Hz, 1H), 8.11-7.82 (m, 5H), 7.82-7.44 (m, 5H), 4.89-4.69 (m,1H), 1.39 (dd, J=6.1, 3.7 Hz, 3H). ES/MS m/z=537.5(M+H⁺);

(S)-3-(2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)-N-ethylbenzenesulfonamide(Compound 39a); ¹H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J=4.9 Hz, 1H),8.44-7.72 (m, 9H), 7.69-7.55 (m, 1H), 7.55-7.42 (m, 1H), 4.80 (d, J=32.4Hz, 2H), 3.26-3.02 (m, 1H), 3.00-2.68 (m, 2H), 1.40 (dd, J=6.6, 4.3 Hz,3H), 1.00 (dt, J=23.1, 7.2 Hz, 3H). ES/MS m/z=601.1(M+H⁺);

(S)-3-(2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzenesulfonamide(Compound 40a); ¹H NMR (400 MHz, DMSO-d6) δ 8.81-8.68 (m, 1H), 8.21-8.02(m, 2H), 8.04-7.72 (m, 7H), 7.65-7.42 (m, 4H), 4.84 (d, J=6.7 Hz, 1H),4.71 (s, 1H), 1.40 (dd, J=17.0, 6.6 Hz, 3H). ES/MS m/z=573(M+H⁺);

(S)-2-(1-(6-amino-5-(pyrimidin-5-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 41a); ¹H NMR (400 MHz, DMSO-d6) δ 9.14 (m, 2H), 8.10 (s, 1H),7.80 (t, J=8.1 Hz, 2H), 7.70-7.48 (m, 3H), 7.46-7.20 (m, 2H), 5.07-4.82(m, 1H), 1.44 (t, J=34.5 Hz, 3H). ES/MS m/z=531.4(M+H⁺);

(S)-2-(1-(6-amino-5-(pyrimidin-5-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 42a); ¹H NMR (400 MHz, DMSO-d6) δ 8.27-8.10 (m, 2H), 7.99 (s,2H), 7.83-7.67 (m, 2H), 7.55 (m, 6H), 4.95-4.77 (m, 1H), 1.45 (d, J=6.8Hz, 3H). ES/MS m/z=495.6(M+H⁺);

(S)-2-(1-(6-amino-5-(pyridin-3-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 43a); ¹H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.60 (s, 1H),8.13 (d, J=12.6 Hz, 2H), 7.90-7.71 (m, 2H), 7.50 (ddd, J=91.6, 25.8, 8.8Hz, 5H), 4.96 (s, 1H), 1.48 (d, J=6.6 Hz, 3H). ES/MS m/z=530.3 (M+H⁺);

(S)-2-(1-(6-amino-5-(pyridin-3-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 44a); ¹H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J=1.3 Hz, 1H), 8.62(dd, J=4.9, 1.7 Hz, 1H), 8.30-8.03 (m, 2H), 7.98 (s, 1H), 7.87-7.69 (m,2H), 7.66-7.30 (m, 6H), 4.93-4.69 (m, 1H), 1.44 (d, J=6.7 Hz, 3H)).ES/MS m/z=494.1 (M+H⁺);

(S)-2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 45a); ¹H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J=4.9 Hz, 1H), 8.09(s, 1H), 7.94 (t, J=7.0 Hz, 1H), 7.89-7.78 (m, 3H), 7.73 (s, 1H), 7.62(dd, J=6.9, 1.7 Hz, 1H), 7.46 (ddd, J=35.6, 32.4, 9.1 Hz, 6H), 5.03-4.84(m, 1H), 1.43 (d, J=6.6 Hz, 3H). ES/MS m/z=529.3 (M+H⁺);

(S)-2-(1-(6-amino-5-((2-aminobenzo[d]thiazol-6-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 46a); ¹H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.06 (s, 1H),7.87 (s, 3H), 7.76 (t, J=7.6 Hz, 1H), 7.64-7.47 (m, 8H), 7.40 (d, J=8.2Hz, 1H), 4.92-4.70 (m, 1H), 1.42 (d, J=6.6 Hz, 3H). ES/MS m/z=565.2(M+H⁺);

(S)-2-(1-(6-amino-5-((3-fluoro-5-methoxyphenyl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 47a); ¹H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.75 (t, J=8.0Hz, 1H), 7.67 (s, 1H), 7.55 (dt, J=24.9, 7.1 Hz, 8H), 7.31-7.18 (m, 2H),6.92 (d, J=11.1 Hz, 1H), 4.85-4.68 (m, 1H), 3.82 (d, J=1.0 Hz, 3H), 1.40(d, J=6.7 Hz, 3H). ES/MS m/z=541.1 (M+H⁺);

(S)-2-(1-(6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 48a); ¹H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J=3.0 Hz, 1H), 7.88(dd, J=8.0, 4.0 Hz, 1H), 7.85-7.71 (m, 4H), 7.64-7.35 (m, 6H), 7.11 (d,J=6.9 Hz, 1H), 6.83 (s, 2H), 4.67 (p, J=6.5 Hz, 1H), 1.24 (d, J=6.6 Hz,3H). ES/MS m/z=512.1 (M+H⁺);

(S)-2-(1-(5-((1H-pyrazol-4-yl)ethynyl)-6-aminopyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 49a); ¹H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 8.01 (s, 2H),7.76 (t, J=7.6 Hz, 2H), 7.66-7.48 (m, 6H), 4.87-4.69 (m, 2H), 1.39 (d,J=6.5 Hz, 3H). ES/MS m/z=483.1 (M+H⁺);

(S)-2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 50a); ¹H NMR (400 MHz, dmso-d6) δ 8.75 (d, J=3.9 Hz, 1H),8.32-8.10 (m, 1H), 8.12-7.70 (m, 5H), 7.73-7.31 (m, 6H), 4.85 (dd,J=13.0, 6.4 Hz, 1H), 1.40 (dd, J=19.9, 6.7 Hz, 3H). ES/MS m/z=494.1(M+H⁺);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-hydroxy-3-phenylquinazolin-4(3H)-one(Compound 52a): ¹H NMR (400 MHz, DMSO-d₆) δ 11.48 (s, 1H), 8.70 (d,J=2.9 Hz, 1H), 8.09 (s, 1H), 7.96-7.82 (m, 3H), 7.78 (t, J=8.2 Hz, 1H),7.70-7.45 (m, 6H), 7.28 (dd, J=8.0, 1.0 Hz, 1H), 6.92 (dd, J=8.2, 1.0Hz, 1H), 4.91-4.80 (m, 1H), 1.35 (d, J=6.5 Hz, 3H). ES/MS 494.2 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-8-methyl-3-phenylquinazolin-4(3H)-one(Compound 53a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.65-8.62 (m, 1H), 8.00 (s,1H), 7.94-7.88 (m, 1H), 7.88-7.80 (m, 1H), 7.65-7.60 (m, 1H), 7.60-7.47(m, 5H), 7.44 (d, J=8.1 Hz, 1H), 7.25 (d, J=7.7 Hz, 2H), 5.00-4.86 (m,1H), 2.41 (s, 3H), 1.33 (d, J=6.5 Hz, 3H). ES/MS 526.1 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylquinazolin-4(3H)-one(Compound 54a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.74-8.69 (m, 1H), 8.08 (s,1H), 7.97-7.91 (m, 1H), 7.90-7.82 (m, 2H), 7.75 (dd, J=8.1, 7.3 Hz, 1H),7.68 (dd, J=8.2, 1.3 Hz, 1H), 7.62-7.37 (m, 6H), 7.34-7.27 (m, 1H),4.85-4.74 (m, 1H), 2.70 (s, 3H), 1.32 (d, J=6.6 Hz, 3H). ES/MS 492.2(M+H⁺);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile(Compound 55a): ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (d, J=1.5 Hz, 1H), 8.78(dd, J=2.6, 1.5 Hz, 1H), 8.63 (d, J=2.6 Hz, 1H), 8.14 (dd, J=7.6, 1.9Hz, 1H), 8.11-8.00 (m, 3H), 7.72 (s, 1H), 7.64-7.41 (m, 6H), 4.90-4.74(m, 1H), 1.36 (d, J=6.6 Hz, 3H). ES/MS 486.2 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8-methyl-3-phenylquinazolin-4(3H)-one(Compound 56a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (dt, J=2.9, 0.7 Hz,1H), 8.06 (s, 1H), 7.98-7.93 (m, 1H), 7.92-7.89 (m, 1H), 7.85 (td,J=8.6, 2.9 Hz, 1H), 7.69 (ddd, J=7.4, 1.6, 0.9 Hz, 1H), 7.59-7.46 (m,7H), 7.43 (t, J=7.6 Hz, 1H), 5.07-4.95 (m, 1H), 2.45 (s, 3H), 1.36 (d,J=6.5 Hz, 3H). ES/MS 492.2 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3-butylphenyl)-5-chloroquinazolin-4(3H)-one(Compound 57a): ¹H NMR (400 MHz, DMSO) δ 8.77-8.67 (m, 1H), 8.11-7.97(m, 1H), 7.97-7.74 (m, 3H), 7.62-7.54 (m, 1H), 7.48-7.37 (m, 2H),7.37-7.24 (m, 3H), 4.90-4.75 (m, 1H), 2.62 (dt, J=26.3, 7.7 Hz, 2H),1.55 (dq, J=24.3, 7.9 Hz, 2H), 1.38-1.22 (m, 5H), 0.87 (dtd, J=22.5,7.4, 1.7 Hz, 3H). ES/MS 568.2 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3-(methylsulfonyl)phenyl)quinazolin-4(3H)-one(Compound 58a): ¹H NMR (400 MHz, DMSO) δ 8.67 (dd, J=6.9, 2.7 Hz, 1H),8.22 (dt, J=9.4, 2.0 Hz, 1H), 8.09-7.96 (m, 1H), 7.96-7.72 (m, 6H), 7.58(ddd, J=7.7, 3.8, 1.6 Hz, 1H), 7.06 (dd, J=35.8, 7.1 Hz, 1H), 6.82 (s,2H), 4.72 (q, J=6.8 Hz, 1H), 3.29 (s, 1.5H), 3.21 (s, 1.5H), 1.36-1.28(m, 3H). ES/MS 590.1 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3-(tert-butyl)phenyl)-5-chloroquinazolin-4(3H)-one(Compound 59a): ¹H NMR (400 MHz, DMSO) δ 8.77-8.68 (m, 1H), 8.11-7.98(m, 1H), 7.99-7.74 (m, 3H), 7.66-7.55 (m, 2H), 7.55-7.40 (m, 3H),7.41-7.29 (m, 1H), 4.95-4.70 (m, 1H), 1.37-1.20 (m, 12H). ES/MS 568.2(M+H⁺);

(S)-3-([1,1′-biphenyl]-3-yl)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloroquinazolin-4(3H)-one(Compound 60a): ¹H NMR (400 MHz, DMSO) δ 8.72 (dd, J=6.0, 2.8 Hz, 1H),8.02 (d, J=2.1 Hz, 1H), 7.99-7.90 (m, 2H), 7.91-7.75 (m, 5H), 7.74-7.60(m, 3H), 7.63-7.53 (m, 2H), 7.54-7.31 (m, 4H), 5.03-4.88 (m, 1H), 1.38(dd, J=6.5, 2.9 Hz, 3H). ES/MS 588.2 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3-ethylphenyl)quinazolin-4(3H)-one(Compound 61a): ¹H NMR (400 MHz, DMSO) δ 8.72 (dd, J=13.0, 2.7 Hz, 1H),8.03 (d, J=19.3 Hz, 1H), 7.97-7.72 (m, 3H), 7.62-7.53 (m, 1H), 7.48-7.39(m, 3H), 7.32 (q, J=10.6, 9.2 Hz, 3H), 4.93-4.74 (m, 1H), 2.73-2.56 (m,2H), 1.38-1.29 (m, 3H), 1.26-1.11 (m, 3H). ES/MS 540.2 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro-5-methyl-3-phenylquinazolin-4(3H)-one(Compound 62a): ¹H NMR (400 MHz, DMSO) δ 8.63 (dt, J=2.8, 0.8 Hz, 1H),8.08 (s, 1H), 7.93-7.79 (m, 2H), 7.74 (br s, 1H), 7.66-7.41 (m, 8H),7.29 (ddd, J=8.3, 5.0, 1.0 Hz, 1H), 4.92-4.84 (m, 1H), 2.65 (s, 3H),1.39 (d, J=6.7 Hz, 3H). ES/MS 510.2 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro-5-methyl-3-phenylquinazolin-4(3H)-one(Compound 63a): ¹H NMR (400 MHz, DMSO) δ 8.03 (s, 1H), 7.78 (td, J=9.6,4.2 Hz, 1H), 7.65-7.41 (m, 7H), 7.34 (td, J=9.8, 3.7 Hz, 1H), 7.24-7.19(m, 2H), 6.90 (dt, J=11.1, 2.4 Hz, 1H), 4.86-4.78 (m, 1H), 3.82 (s, 3H),1.40 (d, J=6.7 Hz, 3H). ES/MS 543.2 (M+H⁺);

(S)-2-(1-((6-amino-5-((3-fluoro-5-methoxyphenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one(Compound 64a): ¹H NMR (400 MHz, DMSO) δ 8.05 (s, 1H), 7.96-7.92 (m,1H), 7.78-7.72 (m, 1H), 7.65-7.34 (m, 7H), 7.22-7.17 (m, 2H), 6.89 (dt,J=11.1, 2.4 Hz, 1H), 4.90-4.83 (m, 1H), 3.80 (s, 3H), 1.41 (d, J=6.7 Hz,3H). ES/MS 525.2 (M+H⁺);

(S)-2-(1-((6-amino-5-((3-fluoro-5-methoxyphenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(Compound 65a): ¹H NMR (400 MHz, DMSO) δ 8.05 (s, 1H), 7.81 (td, J=8.2,5.4 Hz, 1H), 7.66-7.44 (m, 7H), 7.35-7.18 (m, 3H), 6.91 (dt, J=11.1, 2.4Hz, 1H), 4.80-4.71 (m, 1H), 3.81 (s, 3H), 1.39 (d, J=6.7 Hz, 3H). ES/MS525.2 (M+H⁺);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 66a): ¹H NMR (400 MHz, DMSO) δ 8.99 (d, J=1.6 Hz, 1H), 8.72(dd, J=2.6, 1.5 Hz, 1H), 8.60 (d, J=2.6 Hz, 1H), 8.07-7.71 (m, 6H),7.59-7.50 (m, 2H), 7.45-7.25 (m, 3H), 5.01-4.92 (m, 1H), 1.42 (d, J=6.6Hz, 3H). ES/MS 547.2 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-phenylquinazolin-4(3H)-one(Compound 67a): ¹H NMR (400 MHz, DMSO) δ 8.74 (dd, J=3.0, 0.7 Hz, 1H),8.11-7.73 (m, 9H), 7.65-7.47 (m, 6H), 4.90-4.82 (m, 1H), 1.36 (d, J=6.6Hz, 3H). ES/MS 528.2 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-phenyl-5-(trifluoromethyl)quinazolin-4(3H)-one(Compound 68a): ¹H NMR (400 MHz, DMSO) δ 8.75 (dd, J=2.9, 0.8 Hz, 1H),8.21-8.16 (m, 1H), 8.13-8.03 (m, 2H), 8.01-7.92 (m, 2H), 7.87 (td,J=8.7, 2.9 Hz, 1H), 7.62-7.49 (m, 6H), 4.87-4.78 (m, 1H), 1.35 (d, J=6.6Hz, 3H). ES/MS 545.2 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-8-methyl-3-phenylquinazolin-4(3H)-one(Compound 69a): ¹H NMR (400 MHz, DMSO) δ 8.64 (dd, J=3.0, 0.7 Hz, 1H),8.03 (s, 1H), 7.91 (ddd, J=8.7, 4.8, 0.7 Hz, 1H), 7.85 (td, J=8.6, 2.9Hz, 1H), 7.67 (dd, J=8.4, 5.5 Hz, 1H), 7.58-7.30 (m, 8H), 7.20 (dd,J=11.0, 8.3 Hz, 1H), 5.01-4.92 (m, 1H), 2.39 (s, 3H), 1.34 (d, J=6.6 Hz,3H). ES/MS 510.2 (M+H⁺);

(S)-3-(2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-4-oxoquinazolin-3(4H)-yl)benzonitrile(Compound 70a): ¹H NMR (400 MHz, DMSO) δ 8.67 (dd, J=3.1, 2.4 Hz, 1H),8.20 (t, J=1.8 Hz, 1H), 8.11-7.80 (m, 11H), 7.77-7.66 (m, 1H), 4.90-4.82(s, 1H), 1.39 (d, J=6.6 Hz, 3H). ES/MS 553.2 (M+H⁺);

(S)-3-(2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-4-oxoquinazolin-3(4H)-yl)benzonitrile(Compound 71a): ¹H NMR (400 MHz, DMSO) δ 9.00 (dd, J=1.6, 1.0 Hz, 1H),8.72 (dt, J=2.6, 1.7 Hz, 1H), 8.59 (dd, J=2.6, 0.8 Hz, 1H), 8.21-8.17(m, 1H), 8.06-7.82 (m, 8H), 7.75-7.65 (m, 1H), 4.92-4.84 (m, 1H), 1.40(d, J=6.6 Hz, 3H). ES/MS 536.2 (M+H⁺);

(S)-3-(2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro-5-methyl-4-oxoquinazolin-3(4H)-yl)benzonitrile(Compound 72a): ¹H NMR (400 MHz, DMSO) δ 8.60 (d, J=2.8 Hz, 1H), 8.15(dd, J=2.1, 1.5 Hz, 1H), 8.00-7.78 (m, 6H), 7.72-7.55 (m, 2H), 7.34-7.25(m, 2H), 4.93-4.87 (m, 1H), 2.64 (s, 3H), 1.41 (d, J=6.6 Hz, 3H). ES/MS535.2 (M+H⁺);

(S)-3-(2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro-5-methyl-4-oxoquinazolin-3(4H)-yl)benzonitrile(Compound 73a): ¹H NMR (400 MHz, DMSO) δ 8.96 (dd, J=2.9, 1.5 Hz, 1H),8.66 (dd, J=2.6, 1.5 Hz, 1H), 8.58 (d, J=2.6 Hz, 1H), 8.15 (t, J=1.8 Hz,1H), 7.98-7.77 (m, 4H), 7.73-7.54 (m, 2H), 7.40-7.20 (m, 2H), 4.95-4.86(m, 1H), 2.64 (s, 3H), 1.41 (d, J=6.6 Hz, 3H). ES/MS 518.2 (M+H⁺);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)propyl)-5-(difluoromethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 74a): ¹H NMR (400 MHz, DMSO) δ 9.00 (d, J=1.6 Hz, 1H), 8.73(dd, J=2.6, 1.5 Hz, 1H), 8.61 (d, J=2.5 Hz, 1H), 8.04 (s, 1H), 8.03-7.70(m, 4H), 7.65-7.50 (m, 3H), 7.43 (tt, J=9.4, 2.5 Hz, 1H), 7.37-7.29 (m,1H), 4.92-4.83 (m, 1H), 2.01 (ddd, J=14.2, 7.4, 4.8 Hz, 1H), 1.79 (dq,J=15.2, 7.5 Hz, 1H), 0.79 (t, J=7.3 Hz, 3H). ES/MS 561.2 (M+H⁺);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro-5-methyl-3-phenylquinazolin-4(3H)-one(Compound 75a): ¹H NMR (400 MHz, DMSO) δ 8.95 (d, J=1.5 Hz, 1H), 8.68(dd, J=2.6, 1.5 Hz, 1H), 8.61 (d, J=2.6 Hz, 1H), 8.03 (s, 1H), 7.64 (s,1H), 7.59-7.38 (m, 7H), 7.27 (ddd, J=8.4, 5.0, 1.0 Hz, 1H), 4.91-4.82(m, 1H), 2.64 (s, 3H), 1.38 (d, J=6.7 Hz, 3H). ES/MS 493.2 (M+H⁺);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-phenylquinazolin-4(3H)-one(Compound 76a): ¹H NMR (400 MHz, DMSO) δ 9.02 (d, J=1.5 Hz, 1H), 8.77(dd, J=2.6, 1.5 Hz, 1H), 8.63 (d, J=2.6 Hz, 1H), 8.09-7.72 (m, 6H),7.61-7.44 (m, 6H), 4.91-4.83 (m, 1H), 1.36 (d, J=6.7 Hz, 3H). ES/MS511.2 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-(difluoromethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 77a): ¹H NMR (400 MHz, DMSO) δ 8.68 (dt, J=3.0, 0.7 Hz, 1H),8.09-7.71 (m, 8H), 7.62-7.52 (m, 2H), 7.46-7.29 (m, 3H), 5.01-4.92 (m,1H), 1.41 (d, J=6.6 Hz, 3H). ES/MS 564.2 (M+H⁺);

(S)-5-chloro-2-(1-((2,6-diamino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 78a): ¹H NMR (400 MHz, DMSO) δ 8.6 (m, 1H), 7.9-7.4 (m, 8H),6.7 (m, 1H), 6.26 (bs, 1H), 5.98 (bs, 2H), 4.7 (m, 1H), 1.33 (d, J=4 Hz,3H). ES/MS 563.9 (M+H⁺);

(S)-2-(1-((6-amino-5-((3-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one.(Compound 79a): ¹H NMR (400 MHz, DMSO) δ 8.54 (dt, J=4.7, 1.5 Hz, 1H),8.08 (s, 1H), 7.90 (ddd, J=9.3, 8.5, 1.3 Hz, 1H), 7.76 (t, J=8 Hz, 1H),7.65-7.4 (m, 8H), 4.85 (m, 1H), 1.36 (d, J=6.4 Hz, 3H). ES/MS 548.9(M+H⁺);

(S)-2-(1-((6-amino-5-((3-methoxypyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one.(Compound 80a): ¹H NMR (400 MHz, DMSO) δ 8.24 (dd, J=4.7, 1.3 Hz, 1H),8.11 (s, 1H), 7.75 (dd, J=8.5, 7.6 Hz, 1H), 7.65-7.4 (m, 8H), 4.88 (m,1H), 1.38 (d, J=6.7 Hz, 3H). ES/MS 560.9 (M+H⁺);

(S)-2-(1-((6-amino-5-((3-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3-methoxy-2-methylphenyl)quinazolin-4(3H)-one(Compound 81a-1): 1H NMR (400 MHz, DMSO-d6) δ 8.50 (dt, J=4.6, 1.5 Hz,1H), 7.91-7.5 (m, 9H), 7.29 (t, J=8.2 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H),6.99 (d, J=8.4 Hz, 1H), 5.17 (m, 1H), 3.78 (s, 3H), 1.86 (s, 3H), 1.42(d, J=6.6 Hz, 3H). ES/MS 557.0 (M+H⁺);

(S)-2-(1-((6-amino-5-((3-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3-methoxy-2-methylphenyl)quinazolin-4(3H)-one(Compound 81a-2): ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (dt, J=4.7, 1.5 Hz,1H), 8.09 (s, 1H), 7.91 (ddd, J=9.3, 8.5, 1.3 Hz, 1H), 7.83-7.4 (m, 6H),7.28 (t, J=8.1 Hz, 1H), 7.06 (d, J=8.1 Hz, 2H), 4.96 (m, 1H), 3.85 (s,3H), 1.89 (s, 3H), 1.26 (d, J=6.7 Hz, 3H). ES/MS 557.0 (M+H⁺);

(S)-2-(1-((6-amino-5-((3,5-difluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one.(Compound 82a): 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J=2.3 Hz, 1H), 8.16(td, J=9.0, 2.4 Hz, 1H), 8.10 (s, 1H), 7.81-7.4 (m, 8H), 4.86 (p, J=6.7Hz, 1H), 1.36 (d, J=6.7 Hz, 3H). ES/MS 530.9 (M+H⁺)

(S)-5-chloro-2-(1-((2,6-diamino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-phenylquinazolin-4(3H)-one.(Compound 83a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (dt, J=2.9, 0.7 Hz,1H), 7.93-7.71 (m, 4H), 7.65-7.51 (m, 5H), 6.82 (d, J=7.0 Hz, 1H), 6.28(bs, 1H), 5.98 (s, 1H), 4.68 (q, J=6.6 Hz, 1H), 1.23 (d, J=6.4 Hz, 3H).ES/MS 527.9 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)-8-fluoroquinazolin-4(3H)-one(Compound 84a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (dd, J=2.8, 0.9 Hz,1H), 8.08 (s, 1H), 7.92-7.66 (m, 3H), 7.70-7.48 (m, 4H), 7.45-7.06 (m,2H), 5.01 (p, J=6.8 Hz, 1H), 1.45 (d, J=6.6 Hz, 3H). ES/MS 566.5 (M+H⁺);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 85a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (d, J=1.5 Hz, 1H),8.84-8.54 (m, 2H), 8.06 (s, 1H), 7.89-7.70 (m, 2H), 7.68-7.41 (m, 3H),7.52-7.29 (m, 2H), 4.92 (t, J=6.7 Hz, 1H), 1.41 (d, J=6.6 Hz, 3H). ES/MS531.6 (M+H⁺);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(Compound 86a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (d, J=1.7 Hz, 1H),8.88-8.76 (m, 1H), 8.70-8.56 (m, 1H), 8.10 (d, J=2.1 Hz, 1H), 8.03-7.78(m, 2H), 7.78-7.46 (m, 7H), 7.45-7.11 (m, 2H), 5.01-4.76 (m, 1H), 1.35(dd, J=6.6, 2.2 Hz, 3H). ES/MS 479.3 (M+H⁺);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one(Compound 87a), ¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (t, J=1.1 Hz, 1H), 8.74(ddd, J=2.4, 1.5, 0.8 Hz, 1H), 8.62 (dd, J=2.6, 0.7 Hz, 1H), 8.07 (s,1H), 7.99-7.80 (m, 1H), 7.75 (s, 1H), 7.70-7.46 (m, 3H), 7.48-7.13 (m,3H), 4.94 (t, J=6.8 Hz, 2H), 1.42 (d, J=6.6 Hz, 3H). ES/MS 515.6 (M+H+);

(R)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 9b). ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (d, J=2.8 Hz, 1H), 8.11(s, 1H), 7.98-7.68 (m, 4H), 7.70-7.50 (m, 3H), 7.50-7.06 (m, 3H), 4.92(t, J=6.8 Hz, 1H), 1.40 (dd, J=6.4, 1.3 Hz, 3H). ES/MS 548.8 (M+H+);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3-chlorophenyl)quinazolin-4(3H)-one(Compound 89a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (dd, J=3.9, 1.4 Hz,1H), 8.84-8.69 (m, 1H), 8.62 (q, J=2.5 Hz, 1H), 8.05 (d, J=19.0 Hz, 1H),7.91-7.73 (m, 3H), 7.71-7.43 (m, 5H), 4.87 (q, J=6.2 Hz, 1H), 1.38 (t,J=6.5 Hz, 3H). ES/MS 530.4 (M+H+);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one(Compound 90a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (dt, J=2.9, 0.7 Hz,1H), 8.06 (s, 1H), 8.01-7.73 (m, 6H), 7.68-7.36 (m, 6H), 4.85 (q, J=6.6Hz, 1H), 1.33 (d, J=6.6 Hz, 3H). ES/MS 496.5 (M+H+);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one(Compound 91a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (d, J=1.5 Hz, 1H), 8.78(dd, J=2.6, 1.5 Hz, 1H), 8.63 (d, J=2.6 Hz, 1H), 8.06 (s, 1H), 8.01-7.70(m, 4H), 7.71-7.20 (m, 7H), 4.85 (p, J=6.4 Hz, 1H), 1.35 (d, J=6.6 Hz,3H). ES/MS 479.5 (M+H⁺);

(S)-3-(2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzonitrile(Compound 92a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (tt, J=2.9, 0.7 Hz,1H), 8.12-7.68 (m, 10H), 7.61 (dd, J=7.7, 1.3 Hz, 2H), 4.92-4.62 (m,1H), 1.37 (dd, J=6.6, 1.9 Hz, 3H). ES/MS 537.5 (M+H+);

(S)-3-(2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzonitrile(Compound 93a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (t, J=1.5 Hz, 1H), 8.73(ddd, J=2.6, 2.0, 1.5 Hz, 1H), 8.61 (dd, J=2.6, 0.8 Hz, 1H), 8.19 (ddd,J=2.1, 1.6, 0.5 Hz, 1H), 8.06-7.68 (m, 9H), 7.66-7.57 (m, 1H), 5.02-4.74(m, 1H), 1.38 (dd, J=6.6, 2.0 Hz, 3H). ES/MS 521.1 (M+H⁺);

(S)-3-(2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-6-fluoro-4-oxoquinazolin-3(4H)-yl)benzonitrile(Compound 94a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (tt, J=2.9, 0.7 Hz,1H), 8.21 (td, J=1.8, 0.5 Hz, 1H), 8.16-7.64 (m, 10H), 7.50 (s, 1H),4.87 (d, J=6.5 Hz, 1H), 1.53-1.32 (m, 3H). ES/MS 521.6 (M+H+);

(S)-3-(2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-6-fluoro-4-oxoquinazolin-3(4H)-yl)benzonitrile(Compound 95a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.08-8.90 (m, 1H), 8.74 (dt,J=2.6, 1.7 Hz, 1H), 8.67-8.45 (m, 1H), 8.20 (ddd, J=2.1, 1.6, 0.5 Hz,1H), 8.06-7.64 (m, 10H), 7.46 (s, 2H), 4.90 (q, J=6.4 Hz, 1H), 1.40 (dd,J=6.7, 0.9 Hz, 3H). ES/MS 504.4 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3-chlorophenyl)-6-fluoroquinazolin-4(3H)-one(Compound 96a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (ddt, J=5.4, 2.9, 0.7Hz, 1H), 8.06 (d, J=16.9 Hz, 1H), 8.01-7.75 (m, 6H), 7.66-7.38 (m, 6H),4.92 (dd, J=8.3, 5.1 Hz, 1H), 1.38 (t, J=6.4 Hz, 3H). ES/MS 530.8(M+H+);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3-chlorophenyl)-6-fluoroquinazolin-4(3H)-one(Compound 97a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (dd, J=4.4, 1.6 Hz,1H), 8.76 (ddd, J=4.1, 2.6, 1.6 Hz, 1H), 8.63 (t, J=2.3 Hz, 1H), 8.06(d, J=19.3 Hz, 1H), 7.99-7.71 (m, 5H), 7.70-7.38 (m, 5H), 5.01-4.88 (m,1H), 1.40 (dd, J=6.7, 5.5 Hz, 3H). ES/MS 513.9 (M+H+);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylquinazolin-4(3H)-one(Compound 98a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (d, J=1.5 Hz, 1H),8.86-8.69 (m, 1H), 8.63 (dd, J=2.7, 1.5 Hz, 1H), 8.03 (d, J=2.3 Hz, 1H),7.89-7.59 (m, 4H), 7.53 (dt, J=9.8, 3.6 Hz, 6H), 7.31 (d, J=7.2 Hz, 1H),4.79 (t, J=6.9 Hz, 1H), 2.71 (s, 3H), 1.49-1.21 (m, 3H). ES/MS 475.3(M+H+).

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-3-(3-fluorophenyl)quinazolin-4(3H)-one(Compound 99a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (dt, J=2.9, 0.7 Hz,1H), 8.07 (d, J=3.8 Hz, 1H), 8.01-7.80 (m, 2H), 7.85-7.63 (m, 2H),7.66-7.15 (m, 6H), 5.02-4.73 (m, 1H), 1.37 (d, J=6.6 Hz, 3H). ES/MS514.5 (M+H+).

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-8-fluoroquinazolin-4(3H)-one(Compound 100a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (d, J=1.5 Hz, 1H),8.68 (dd, J=2.6, 1.5 Hz, 1H), 8.60 (d, J=2.5 Hz, 1H), 8.07 (s, 1H),8.05-7.85 (m, 1H), 7.85-7.68 (m, 2H), 7.55 (ddt, J=15.8, 7.9, 3.6 Hz,3H), 7.46-7.32 (m, 1H), 7.32-7.17 (m, 1H), 5.05 (t, J=6.9 Hz, 1H), 1.47(d, J=6.6 Hz, 3H). ES/MS 515.3 (M+H⁺).

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-3-(3-fluorophenyl)quinazolin-4(3H)-one(Compound 101a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (t, J=1.5 Hz, 1H),8.76 (ddd, J=2.4, 1.4, 0.6 Hz, 1H), 8.63 (d, J=2.6 Hz, 1H), 8.08 (d,J=5.1 Hz, 1H), 7.96-7.73 (m, 2H), 7.75-7.55 (m, 3H), 7.53-7.22 (m, 4H),4.86 (dq, J=13.6, 6.8 Hz, 1H), 1.38 (d, J=6.6 Hz, 3H). ES/MS 497.5(M+H+);

(S)-2-(1-((6-amino-5-(pyrimidin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 102a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.02-8.84 (m, 1H), 8.07 (s,1H), 7.92-7.75 (m, 2H), 7.73-7.48 (m, 7H), 7.45 (d, J=19.5 Hz, 2H), 4.80(t, J=6.7 Hz, 1H), 1.32 (d, J=6.6 Hz, 3H). ES/MS 495.7 (M+H+);

(S)-2-(1-((6-amino-5-(pyrimidin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 103a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.06-8.78 (m, 2H), 8.10 (s,1H), 7.97-7.72 (m, 3H), 7.75-7.51 (m, 3H), 7.51-7.31 (m, 3H), 4.93 (t,J=6.7 Hz, 1H), 1.41 (d, J=6.6 Hz, 3H). ES/MS 531.8 (M+H+);

(S)-2-(1-((6-amino-5-(pyrimidin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylquinazolin-4(3H)-one(Compound 104a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.02-8.83 (m, 2H), 8.09 (s,1H), 7.92 (s, 1H), 7.82-7.66 (m, 2H), 7.61-7.46 (m, 6H), 7.31 (ddd,J=7.3, 1.4, 0.9 Hz, 1H), 4.81 (p, J=6.6 Hz, 1H), 2.84-2.62 (m, 3H), 1.32(d, J=6.6 Hz, 3H). ES/MS 475.6(M+H+);

(S)-2-(1-((6-amino-5-(pyrimidin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-5-methylquinazolin-4(3H)-one(Compound 105a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (d, J=4.9 Hz, 2H),8.13 (s, 1H), 7.90 (s, 1H), 7.84-7.65 (m, 2H), 7.65-7.52 (m, 3H),7.49-7.27 (m, 4H), 5.07-4.89 (m, 1H), 2.72 (d, J=5.9 Hz, 3H), 1.51-1.28(m, 3H). ES/MS 511.3(M+H⁺);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3-fluorophenyl)-5-methylquinazolin-4(3H)-one(Compound 106a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.04 (t, J=1.4 Hz, 1H),8.78 (ddd, J=2.5, 1.5, 0.8 Hz, 1H), 8.69-8.57 (m, 1H), 8.23-8.07 (m,1H), 7.95 (s, 1H), 7.82-7.52 (m, 4H), 7.51-7.08 (m, 4H), 4.88 (tt,J=12.6, 6.6 Hz, 1H), 2.72 (d, J=6.2 Hz, 3H), 1.60-1.20 (m, 3H). ES/MS493.5(M+H+);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)propyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one(Compound 107a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (d, J=1.5 Hz, 1H),8.76 (dd, J=2.6, 1.5 Hz, 1H), 8.69-8.53 (m, 1H), 8.06 (d, J=5.8 Hz, 1H),7.98-7.80 (m, 1H), 7.70-7.29 (m, 8H), 4.86 (q, J=7.2 Hz, 1H), 2.15-1.92(m, 1H), 1.79 (dt, J=14.5, 7.5 Hz, 1H), 0.80 (t, J=7.3 Hz, 3H). ES/MS529.6(M+H⁺);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)propyl)-3-(3,5-difluorophenyl)-5-methylquinazolin-4(3H)-one(Compound 108a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (d, J=1.4 Hz, 1H),8.86-8.69 (m, 1H), 8.76-8.58 (m, 1H), 8.15 (d, J=6.2 Hz, 1H), 7.93-7.70(m, 3H), 7.66-7.51 (m, 2H), 7.49-7.24 (m, 3H), 4.88 (d, J=5.5 Hz, 1H),2.72 (d, J=5.2 Hz, 3H), 2.09-1.92 (m, 1H), 1.80 (dt, J=14.7, 7.4 Hz,1H), 0.80 (t, J=7.4 Hz, 3H). ES/MS 525.5(M+H+);

(S)-2-(1-((6-amino-5-(pyrimidin-2-ylethynyl)pyrimidin-4-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one(Compound 109a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.04-8.86 (m, 2H), 8.01 (d,J=60.1 Hz, 1H), 7.98-7.72 (m, 2H), 7.77-7.63 (m, 1H), 7.66-7.49 (m, 4H),7.43-7.22 (m, 3H), 4.83 (p, J=6.6 Hz, 1H), 1.35 (d, J=6.6 Hz, 3H). ES/MS479.5(M+H⁺);

(S)-3-(2-(1-((6-amino-5-(phenylethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-4-oxoquinazolin-3(4H)-yl)benzonitrile(Compound 110a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (d, J=13.2 Hz, 1H),8.04-7.78 (m, 4H), 7.81-7.63 (m, 3H), 7.68-7.17 (m, 8H), 4.86 (dd,J=9.8, 5.0 Hz, 1H), 1.44 (d, J=6.6 Hz, 3H). ES/MS 502.4 (M+H⁺);

(S)-2-(1-((6-amino-5-(phenylethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-3-(3-fluorophenyl)quinazolin-4(3H)-one(Compound 111a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (dd, J=5.4, 2.0 Hz,1H), 7.99-7.68 (m, 5H), 7.68-7.53 (m, 3H), 7.53-7.17 (m, 7H), 4.87 (q,J=7.6 Hz, 1H), 1.43 (dd, J=6.7, 2.0 Hz, 3H). ES/MS 435.6 (M+H+);

(S)-2-(1-((6-amino-5-(phenylethynyl)pyrimidin-4-yl)amino)ethyl)-5-(methylsulfonyl)-3-phenylquinazolin-4(3H)-one(Compound 112a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (dd, J=7.7, 1.3 Hz,1H), 8.16-7.99 (m, 2H), 7.93 (dd, J=8.2, 1.3 Hz, 1H), 7.82-7.66 (m, 2H),7.66-7.20 (m, 9H), 4.95-4.73 (m, 1H), 3.46 (s, 3H), 1.41 (d, J=6.8 Hz,3H). ES/MS 536.3 (M+H+);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-(methylsulfonyl)-3-phenylquinazolin-4(3H)-one(Compound 113a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.11-8.91 (m, 1H), 8.76(ddd, J=2.5, 1.6, 0.7 Hz, 1H), 8.72-8.52 (m, 1H), 8.42-8.21 (m, 1H),8.24-7.96 (m, 3H), 7.75-7.22 (m, 7H), 4.83 (t, J=6.7 Hz, 1H), 3.63 (s,3H), 1.35 (d, J=6.7 Hz, 3H). ES/MS 539.3(M+H⁺).

(S)-2-(1-((6-amino-5-(phenylethynyl)pyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile(Compound 114a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.16-8.01 (m, 1H),8.01-7.80 (m, 3H), 7.82-7.64 (m, 3H), 7.68-7.29 (m, 10H), 4.94-4.71 (m,1H), 1.39 (d, J=6.7 Hz, 3H). ES/MS 484.6(M+H+);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-3-(pyridin-3-yl)quinazolin-4(3H)-one(Compound 115a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (d, J=1.5 Hz, 1H),8.83-8.47 (m, 3H), 8.19-7.96 (m, 2H), 7.88 (td, J=8.2, 5.4 Hz, 2H),7.70-7.39 (m, 3H), 7.46-7.22 (m, 2H), 4.76 (dt, J=20.3, 6.8 Hz, 1H),1.36 (t, J=6.7 Hz, 3H). ES/MS 480.2(M+H+);

(S)-2-(1-((6-amino-5-(phenylethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-3-(pyridin-3-yl)quinazolin-4(3H)-one(Compound 116a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.88-8.74 (m, 1H),8.76-8.49 (m, 2H), 8.17-7.99 (m, 2H), 8.06-7.78 (m, 2H), 7.84-7.48 (m,4H), 7.50-7.18 (m, 4H), 4.80 (q, J=6.8 Hz, 1H), 1.58-1.37 (m, 3H). ES/MS478.4(M+H⁺).

(S)-2-(1-((6-amino-5-(pyrimidin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(pyridin-3-yl)quinazolin-4(3H)-one(Compound 117a). ¹H NMR (400 MHz, DMSO-d₆) δ 8.95-8.56 (m, 3H),8.17-7.92 (m, 1H), 7.91-7.31 (m, 6H), 7.27-6.88 (m, 3H), 5.02-4.67 (m,1H), 1.54-1.17 (m, 3H). ES/MS 497.1(M+H+);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(pyridin-3-yl)quinazolin-4(3H)-one(Compound 118a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (d, J=1.5 Hz, 1H),8.91-8.45 (m, 4H), 8.14-7.91 (m, 2H), 7.87-7.64 (m, 2H), 7.68-7.36 (m,4H), 4.88-4.65 (m, 1H), 1.36 (t, J=7.1 Hz, 3H). ES/MS 496.8 (M+H+);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-(pyridin-3-yl)quinazolin-4(3H)-one(Compound 119a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (q, J=1.5 Hz, 1H),8.95-8.37 (m, 4H), 8.02 (dddt, J=25.3, 8.1, 2.7, 1.4 Hz, 1H), 7.94-7.80(m, 1H), 7.78-7.39 (m, 3H), 7.45-7.15 (m, 2H), 6.94 (s, 2H), 4.81-4.51(m, 1H), 2.69 (s, 3H), 1.31 (ddd, J=8.1, 6.4, 1.2 Hz, 3H). ES/MS 476.6(M+H⁺);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(5-fluoropyridin-3-yl)-5-methylquinazolin-4(3H)-one(Compound 120a). ¹H NMR (400 MHz, DMSO-d₆) δ 9.16-8.83 (m, 1H),8.83-8.44 (m, 4H), 8.28-7.89 (m, 1H), 7.82 (dd, J=4.7, 1.7 Hz, 1H),7.80-7.46 (m, 2H), 7.31 (dt, J=7.5, 1.3 Hz, 1H), 7.20-7.04 (m, 1H), 6.90(s, 2H), 4.83 (dddd, J=15.4, 13.3, 7.4, 5.6 Hz, 1H), 2.69 (d, J=1.8 Hz,3H), 1.36 (dd, J=7.1, 5.4 Hz, 3H). ES/MS 494.5 (M+H+);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-morpholinoquinazolin-4(3H)-one(Compound 121a): ¹H NMR (400 MHz, DMSO) δ 8.71 (d, J=2.9 Hz, 1H), 8.18(s, 1H), 7.97-7.73 (m, 5H), 7.53 (dt, J=7.3, 1.3 Hz, 1H), 5.63 (p, J=6.7Hz, 1H), 4.03 (td, J=11.4, 3.1 Hz, 1H), 3.94-3.79 (m, 3H), 3.56 (dd,J=12.4, 10.0 Hz, 1H), 3.49-3.38 (m, 1H), 3.09 (d, J=10.7 Hz, 1H), 2.99(dd, J=10.7, 2.4 Hz, 1H), 1.53 (d, J=6.6 Hz, 3H). ES/MS 521.2 (M+H⁺);

(S)-2-(1-((6-amino-5-((3-fluoro-5-methoxyphenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-morpholinoquinazolin-4(3H)-one(Compound 122a): ¹H NMR (400 MHz, DMSO) δ 8.14 (s, 1H), 7.83 (s, 1H),7.67 (t, J=8.2 Hz, 1H), 7.55-7.43 (m, 4H), 7.24-7.16 (m, 2H), 6.90 (dt,J=11.2, 2.5 Hz, 1H), 5.73 (p, J=6.8 Hz, 1H), 4.06-3.76 (m, 5H), 3.55 (t,J=10.8 Hz, 1H), 3.48-3.37 (m, 1H), 3.12 (d, J=10.5 Hz, 1H), 2.98 (d,J=10.9 Hz, 1H), 2.51 (s, 1H), 2.46 (s, 4H), 1.56 (d, J=6.7 Hz, 3H).ES/MS 550.2 (M+H+);

(S)—N-(3-(2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzyl)methanesulfonamide(Compound 123a): ¹H NMR (400 MHz, DMSO) δ 9.01 (dd, J=2.6, 1.5 Hz, 1H),8.75 (ddt, J=9.9, 2.5, 1.1 Hz, 1H), 8.66-8.58 (m, 1H), 8.02 (d, J=5.5Hz, 1H), 7.86-7.40 (m, 10H), 4.83-4.70 (m, 1H), 4.20 (dd, J=20.5, 6.4Hz, 2H), 2.84 (d, J=30.7 Hz, 3H), 1.38-1.29 (m, 3H). ES/MS 602.2 (M+H⁺);

2-((S)-1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)quinazolin-4(3H)-one(Compound 124a): ¹H NMR (400 MHz, DMSO) δ 9.67 (d, J=5.7 Hz, 1H), 9.05(d, J=1.5 Hz, 1H), 8.81 (dd, J=2.6, 1.5 Hz, 1H), 8.61 (d, J=2.6 Hz, 1H),8.08 (s, 1H), 7.90 (dd, J=8.2, 1.3 Hz, 1H), 7.82 (t, J=8.0 Hz, 2H), 7.56(dd, J=7.7, 1.3 Hz, 1H), 7.28 (s, 2H), 5.34 (p, J=6.4 Hz, 1H), 4.78 (p,J=9.7 Hz, 1H), 3.98-3.89 (m, 2H), 2.74-2.60 (m, 4H), 2.47 (dt, J=3.7,1.9 Hz, 12H), 2.42-2.29 (m, 4H), 2.28-2.08 (m, 3H), 1.52 (d, J=6.4 Hz,3H). ES/MS 542.2 (M+H+);

2-((S)-1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)quinazolin-4(3H)-one(Compound 125a): ¹H NMR (400 MHz, DMSO) δ 9.77-9.54 (m, 1H), 9.05 (dd,J=4.6, 1.6 Hz, 1H), 8.88-8.75 (m, 1H), 8.62 (dd, J=4.6, 2.5 Hz, 1H),8.08 (d, J=4.6 Hz, 1H), 7.91 (dd, J=7.7, 4.3 Hz, 1H), 7.82 (ddd, J=9.1,6.8, 3.9 Hz, 2H), 7.63-7.45 (m, 1H), 7.26 (s, 2H), 5.35 (q, J=6.2 Hz,1H), 4.86-4.65 (m, 2H), 3.93 (d, J=8.3 Hz, 3H), 2.77-2.57 (m, 4H), 2.34(d, J=5.3 Hz, 1H), 2.14 (d, J=5.4 Hz, 1H), 1.52 (dd, J=6.5, 4.4 Hz, 3H),1.21 (s, 1H). ES/MS 542.2 (M+H+);

(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-3-(azepan-1-yl)-5-chloroquinazolin-4(3H)-one(Compound 126a): ¹H NMR (400 MHz, DMSO) δ 9.03 (d, J=1.5 Hz, 1H), 8.77(ddd, J=2.5, 1.6, 0.6 Hz, 1H), 8.62 (d, J=2.6 Hz, 1H), 8.17 (s, 1H),7.83-7.66 (m, 3H), 7.57 (s, 3H), 7.54-7.44 (m, 1H), 5.79 (p, J=6.6 Hz,1H), 3.77 (td, J=8.0, 4.4 Hz, 1H), 3.62 (ddd, J=12.2, 8.9, 2.8 Hz, 1H),3.17 (ddd, J=40.9, 12.6, 5.9 Hz, 3H), 1.78-1.45 (m, 15H). ES/MS 516.2(M+H+);

(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(piperazin-1-yl)quinazolin-4(3H)-one(Compound 127a): ¹H NMR (400 MHz, DMSO) δ 8.84 (d, J=11.4 Hz, 1H), 8.61(d, J=14.8 Hz, 1H), 8.13-8.04 (m, 1H), 7.97-7.73 (m, 3H), 7.64-7.48 (m,2H), 7.37 (s, 2H), 7.28 (s, 1H), 5.64-5.56 (m, 1H), 4.17 (t, J=12.6 Hz,1H), 4.04 (t, J=12.7 Hz, 1H), 3.46-3.25 (m, 4H), 3.14 (t, J=13.8 Hz,1H), 2.97 (d, J=12.2 Hz, 1H), 2.47 (d, J=10.1 Hz, 1H), 2.38 (s, 1H),1.55-1.43 (m, 3H). ES/MS 520.2 (M+H⁺);

(S)—N-(3-(2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-methyl-4-oxoquinazolin-3(4H)-yl)benzyl)-N-methylmethanesulfonamide(Compound 128a): ¹H NMR (400 MHz, DMSO) δ 8.70 (dd, J=5.8, 2.9 Hz, 1H),8.02 (d, J=9.6 Hz, 1H), 7.97-7.40 (m, 9H), 7.30 (dd, J=7.5, 4.1 Hz, 1H),4.79 (td, J=7.0, 4.0 Hz, 1H), 4.35-4.19 (m, 2H), 2.94 (d, J=16.5 Hz,3H), 2.73-2.62 (m, 6H), 1.31 (d, J=6.6 Hz, 3H). ES/MS 613.2 (M+H+);

(S)—N-(3-(2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzyl)-N-methylmethanesulfonamide(Compound 129a): ¹H NMR (400 MHz, DMSO) δ 8.74-8.67 (m, 1H), 8.01 (d,J=9.0 Hz, 1H), 7.97-7.69 (m, 5H), 7.61-7.40 (m, 6H), 4.79 (q, J=6.7, 6.2Hz, 1H), 4.34-4.20 (m, 2H), 3.33 (s, 6H), 2.94 (d, J=17.3 Hz, 3H), 2.70(s, 2H), 2.64 (s, 2H), 1.31 (dd, J=6.8, 2.2 Hz, 3H). ES/MS 633.2 (M+H⁺);

(S)—N-(3-(2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzyl)methanesulfonamide(Compound 130a): ¹H NMR (400 MHz, DMSO) δ 8.71 (dd, J=11.2, 2.9 Hz, 1H),8.05 (d, J=3.1 Hz, 1H), 7.97-7.61 (m, 7H), 7.61-7.39 (m, 7H), 7.33 (s,3H), 4.84-4.72 (m, 1H), 4.21 (dd, J=19.7, 6.4 Hz, 2H), 2.84 (d, J=30.6Hz, 3H), 1.33 (dd, J=8.5, 6.5 Hz, 3H), 1.20 (dt, J=12.5, 6.7 Hz, 1H).ES/MS 619.2 (M+H+);

(S)—N-(3-(2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzyl)-2-methylpropane-1-sulfonamide(Compound 131a): ¹H NMR (400 MHz, DMSO) δ 8.70 (dd, J=16.9, 2.9 Hz, 1H),8.03 (d, J=10.0 Hz, 1H), 7.97-7.66 (m, 5H), 7.63-7.35 (m, 7H), 4.77 (dt,J=13.3, 6.7 Hz, 1H), 4.19 (dd, J=20.8, 6.4 Hz, 2H), 2.89-2.67 (m, 2H),2.01 (dh, J=27.2, 6.8 Hz, 1H), 1.33 (dd, J=12.5, 6.7 Hz, 3H), 1.01-0.85(m, 7H). ES/MS 661.2 (M+H+);

(S)-2-(1-((6-amino-5-((5-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 132a): ¹H NMR (400 MHz, DMSO-d₆) δ 9.09-9.03 (m, 1H), 8.32(dd, J=8.3, 2.4 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.90-7.82(m, 2H), 7.67-7.42 (m, 6H), 7.36 (s, 2H), 4.78 (t, J=6.7 Hz, 1H), 1.32(d, J=6.6 Hz, 3H). ES/MS 562.1 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-methylpyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 133a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, J=1.8 Hz, 1H),7.91-7.79 (m, 3H), 7.76-7.64 (m, 2H), 7.63-7.49 (m, 5H), 7.16 (d, J=7.0Hz, 1H), 6.82 (s, 2H), 4.72 (t, J=6.7 Hz, 1H), 2.35 (s, 3H), 1.29 (d,J=6.6 Hz, 3H).). ES/MS 508.1 (M+H⁺);

(S)-2-(1-((6-amino-5-((5-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 134a): ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.33-8.25 (m,1H), 8.11-8.04 (m, 1H), 7.99 (s, 1H), 7.91-7.76 (m, 2H), 7.60 (dt,J=7.7, 1.3 Hz, 1H), 7.57-7.23 (m, 4H), 4.96-4.80 (m, 1H), 4.23-3.43(brs, 2H), 1.39 (dd, J=6.8, 1.2 Hz, 4H). ES/MS 598.1 (M+H⁺).

(S)-6-((4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)nicotinamide(Compound 135a): ¹H NMR (400 MHz, DMSO-d₆) δ 9.12-9.06 (m, 1H),8.31-8.20 (m, 2H), 8.05 (s, 1H), 7.96-7.89 (m, 1H), 7.90-7.80 (m, 2H),7.69 (s, 1H), 7.61 (ddd, J=5.7, 3.3, 0.7 Hz, 1H), 7.54 (d, J=8.9 Hz,1H), 7.47-7.33 (m, 3H), 4.90 (t, J=6.8 Hz, 1H), 4.12 (brs, 5H), 1.40 (d,J=6.6 Hz, 3H). ES/MS 537.1 (M+H+);

(S)-6-((4-amino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)nicotinamide(Compound 136a): ¹H NMR (400 MHz, DMSO-d₆) δ 9.12 (d, J=2.2 Hz, 1H),8.33-8.21 (m, 2H), 8.03 (s, 1H), 7.99-7.79 (m, 3H), 7.70 (s, 1H),7.63-7.49 (m, 6H), 4.86-4.69 (m, 1H), 4.37-3.20 (br m, 2H), 1.32 (dd,J=6.9, 1.3 Hz, 3H). ES/MS 573.1 (M+H⁺).

(S)-isopropyl6-((4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)nicotinate(Compound 137a): ¹H NMR (400 MHz, DMSO-d₆) δ 9.13 (d, J=5.1 Hz, 1H),8.33 (dd, J=7.9, 5.1 Hz, 1H), 8.00 (t, J=6.7 Hz, 2H), 7.83 (dd, J=13.8,6.4 Hz, 2H), 7.67-7.05 (m, 6H), 5.25-5.08 (m, 1H), 4.78 (dd, J=13.5, 6.2Hz, 1H), 4.13-3.35 (m, 4H), 2.35 (d, J=28.1 Hz, 6H), 1.42-1.21 (m, 3H).ES/MS 580.1 (M+H+).

(S)-6-((4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)nicotinicacid (Compound 138a): ¹H NMR (400 MHz, DMSO-d₆) δ 9.19-9.04 (m, 1H),8.32 (dd, J=8.2, 2.3 Hz, 1H), 7.98 (d, J=8.1 Hz, 2H), 7.89-7.73 (m, 2H),7.61-7.45 (m, 7H), 4.77 (s, 1H), 3.55 (brs, 4H), 1.38-1.27 (m, 3H).ES/MS 538.1 (M+H⁺);

(R)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)-2-hydroxyethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 139a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (d, J=2.9 Hz, 1H),8.03 (s, 1H), 8.01-7.93 (m, 1H), 7.93-7.80 (m, 3H), 7.68-7.25 (m, 12H),4.87 (q, J=5.2 Hz, 1H), 4.02-3.43 (m, 2H). ES/MS 528.1 (M+H+);

(S)-2-(1-((6-amino-5-((5-fluoro-6-methylpyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 140a): ¹H NMR (400 MHz, DMSO-d₆) δ 10.36 (d, J=2.7 Hz, 1H),9.22 (s, 1H), 8.49 (s, 1H), 7.98 (d, J=2.8 Hz, 1H), 7.71-7.39 (m, 6H),7.30 (m, 4H), 7.07 (td, J=7.3, 2.5 Hz, 1H), 4.38 (d, J=6.9 Hz, 1H),1.56-1.05 (m, 6H). ES/MS 526.1 (M+H⁺);

(S)-2-(1-((6-amino-5-((6-methylpyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 141a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (s, 1H), 7.86-7.67 (m,3H), 7.67-7.46 (m, 7H), 7.33 (d, J=7.6 Hz, 1H), 4.78 (m, 1H), 3.52 (s,7H), 1.33 (dd, J=6.5, 1.9 Hz, 3H). ES/MS 508.1 (M+H+);

(S)-2-(1-((6-amino-5-((3-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 142a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (dt, J=5.2, 0.8 Hz,1H), 8.33-8.24 (m, 1H), 8.01 (s, 1H), 7.77 (t, J=8.0 Hz, 1H), 7.69-7.40(m, 9H), 7.12 (m, 1H), 4.84 (t, J=6.7 Hz, 1H), 4.31-3.56 (m, 2H), 1.33(dd, J=6.7, 0.9 Hz, 3H). ES/MS 562.1 (M+H⁺);

(S)-2-(1-((6-amino-5-((3-methylpyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 143a)¹H NMR (400 MHz, DMSO-d₆) δ 8.58-8.49 (m, 1H), 8.04 (s,1H), 7.85-7.80 (m, 1H), 7.80-7.73 (m, 1H), 7.64 (dd, J=8.2, 1.2 Hz, 1H),7.60-7.46 (m, 7H), 7.39 (dd, J=7.8, 4.9 Hz, 1H), 4.91-4.75 (m, 1H), 3.69(s, 3H), 2.54-2.49 (m, 3H), 1.34 (d, J=6.6 Hz, 3H). ES/MS 508.1 (M+H+).

(S)-2-(1-((6-amino-5-(cyclopentylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 144a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (d, J=3.3 Hz, 1H),7.81 (dd, J=8.3, 7.7 Hz, 1H), 7.60 (p, J=1.2 Hz, 1H), 7.58-7.55 (m, 2H),7.52 (td, J=3.3, 1.9 Hz, 3H), 7.24 (brs, 2H), 4.79 (t, J=6.7 Hz, 1H),3.55 (d, J=41.9 Hz, 3H), 3.02 (p, J=7.7 Hz, 1H), 2.03 (t, J=8.4 Hz, 2H),1.85-1.69 (m, 4H), 1.62 (m, 2H), 1.31 (d, J=6.6 Hz, 3H). ES/MS 485.2(M+H⁺);

(S)-2-(1-((6-amino-5-(cyclohexylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 145a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (d, J=3.6 Hz, 1H),7.80 (dd, J=8.3, 7.7 Hz, 1H), 7.62-7.46 (m, 9H), 7.18 (brs, 2H),4.87-4.72 (m, 1H), 2.75 (d, J=9.8 Hz, 1H), 1.93 (m, 2H), 1.72 (d, J=6.9Hz, 2H), 1.57 (m, 4H), 1.44-1.27 (m, 5H). ES/MS 499.2 (M+H+);

(R)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)-2-methoxyethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 146a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (t, J=2.9 Hz, 1H),7.52-7.48 (m, 1H), 7.41-7.15 (m, 5H), 7.09 (ddt, J=8.2, 2.6, 1.2 Hz,1H), 6.96 (ddt, J=7.8, 2.6, 1.2 Hz, 1H), 6.89-6.82 (m, 1H), 6.76 (ddd,J=11.7, 8.7, 2.6 Hz, 1H), 6.70-6.59 (m, 1H), 5.62-4.73 (brs, 2H), 4.54(td, J=6.7, 5.4, 3.1 Hz, 1H), 3.17 (m, 1H), 3.11-3.01 (m, 1H), 1.83 (dt,J=3.7, 1.8 Hz, 3H). ES/MS 578.1 (M+H⁺);

(S)-2-(1-((6-amino-5-((4-methylpyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 147a);

(S)-2-(1-((6-amino-5-((4-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 148a): ¹H NMR (400 MHz, DMSO-d₆) δ 10.64 (s, 1H), 10.42 (d,J=6.9 Hz, 1H), 7.82 (td, J=8.0, 0.9 Hz, 1H), 7.74-7.51 (m, 8H), 6.55(brs, 1H), 4.95-4.84 (m, 1H), 2.54-2.43 (m, 4H), 1.34 (dd, J=6.5, 1.0Hz, 3H). ES/MS 562.1 (M+H⁺);

(S)-2-(1-((6-amino-5-((4-(difluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 149a);

(S)-2-(1-((6-amino-5-((4-ethylpyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 150a);

(S)-2-(1-((6-amino-5-((6-(trifluoromethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 151a);

(S)-2-(1-((5-((3-acetylpyridin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 152a);

(S)-2-(1-((5-((6-acetylpyridin-2-yl)ethynyl)-6-aminopyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 153a);

(S)-2-(1-((6-amino-5-((4-(hydroxymethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 154a);

(S)-2-(1-((6-amino-5-((6-(hydroxymethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 155a);

(S)-2-((4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)isonicotinamide(Compound 156a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (dt, J=5.1, 0.8 Hz,1H), 8.34 (s, 1H), 8.28 (dt, J=1.8, 1.0 Hz, 1H), 8.13 (d, J=6.6 Hz, 1H),8.01-7.77 (m, 5H), 7.74-7.45 (m, 7H), 4.90-4.75 (m, 1H), 1.36 (dd,J=6.6, 1.1 Hz, 3H), 1.24 (s, 2H). ES/MS 536.2 (M+H⁺);

2-((1S)-1-((6-amino-5-((6-(1-hydroxyethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 157a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (s, 1H), 8.07 (t,J=8.6 Hz, 1H), 7.94 (t, J=7.8 Hz, 1H), 7.91-7.82 (m, 1H), 7.83-7.68 (m,3H), 7.65-7.48 (m, 9H), 4.85 (m, 2H), 1.48-1.34 (m, 7H). ES/MS 538.1(M+H⁺);

(S)-methyl2-((4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)isonicotinate(Compound 158a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (dd, J=5.1, 1.0 Hz,1H), 8.40 (dt, J=1.7, 0.9 Hz, 1H), 8.20 (s, 1H), 7.96 (ddd, J=8.2, 1.3,0.5 Hz, 1H), 7.92-7.83 (m, 3H), 7.67-7.51 (m, 9H), 4.86 (t, J=7.2 Hz,1H), 3.94 (s, 3H), 1.37 (dd, J=6.7, 1.9 Hz, 3H). ES/MS 552.1 (M+H⁺);

(S)-2-(1-((6-amino-5-((6-(aminomethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 159a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (s, 3H), 8.02-7.92 (m,2H), 7.87 (d, J=7.7 Hz, 1H), 7.77 (td, J=8.0, 0.8 Hz, 1H), 7.66-7.45 (m,8H), 7.17 (s, 1H), 7.08 (s, 2H), 4.74 (p, J=6.6 Hz, 1H), 4.25 (q, J=5.8Hz, 2H), 1.35 (d, J=6.6 Hz, 3H). ES/MS 522.2 (M+H⁺);

(S)-2-((4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)isonicotinicacid (Compound 160a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (dt, J=5.1, 0.9Hz, 1H), 8.36 (dt, J=1.7, 0.8 Hz, 1H), 8.07 (s, 1H), 7.96 (dt, J=8.3,1.0 Hz, 1H), 7.91-7.70 (m, 3H), 7.66-7.47 (m, 10H), 4.81 (t, J=6.6 Hz,1H), 1.34 (d, J=6.6 Hz, 3H). ES/MS 538.2 (M+H⁺);

(S)-2-(1-((5-((3-acetylphenyl)ethynyl)-6-aminopyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 161a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (d, J=5.4 Hz, 1H),7.82-7.69 (m, 4H), 7.68-7.46 (m, 9H), 7.46-7.31 (m, 2H), 4.87-4.77 (m,1H), 4.55 (s, 3H), 1.38 (d, J=6.5 Hz, 3H). ES/MS 536.1 (M+H⁺);

(S)-2-(1-((6-amino-5-((3-(hydroxymethyl)phenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 162a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.35-8.29 (m, 1H), 8.10 (s,1H), 8.02 (dt, J=8.1, 2.1 Hz, 2H), 7.77 (m, 3H), 7.67-7.48 (m, 10H),4.80 (q, J=6.8 Hz, 1H), 2.63 (d, J=0.8 Hz, 2H), 1.41 (d, J=6.7 Hz, 3H).ES/MS 524.1 (M+H⁺);

(S)-2-(1-((6-amino-5-((3-(hydroxymethyl)pyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one(Compound 163a): ¹H NMR (400 MHz, DMSO-d₆) δ 10.53 (s, 1H), 9.56 (s,1H), 8.66 (d, J=5.0 Hz, 1H), 8.14 (s, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.74(d, J=8.2 Hz, 1H), 7.61 (d, J=8.1 Hz, 2H), 7.54-7.26 (m, 5H), 7.11 (m,1H), 5.93 (d, J=0.9 Hz, 1H), 5.47 (s, 2H), 4.87 (m, 1H), 3.84 (brs, 2H),1.39 (d, J=7.1 Hz, 3H). ES/MS 524.1 (M+H⁺); and

(S)-2-(1-((6-amino-5-((5-methylpyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one(Compound 164a).

BIOLOGICAL EXAMPLES

Activity testing was conducted in the Examples below using methodsdescribed herein and those well known in the art.

Example B1 Enzymatic Activity of PI3K Isoforms

Enzymatic activity of the class I PI3K isoforms was measured using atime-resolved fluorescence resonance energy transfer (TR-FRET) assaythat monitors formation of the product 3,4,5-inositol triphosphatemolecule (PIP3), as it competes with fluorescently labeled PIP3 forbinding to the GRP-1 pleckstrin homology domain protein. An increase inphosphatidylinositide 3-phosphate product results in a decrease inTR-FRET signal as the labeled fluorophore is displaced from the GRP-1protein binding site.

Class I PI3K isoforms were expressed and purified as heterodimericrecombinant proteins. All assay reagents and buffers for the TR-FRETassay were purchased from Millipore. PI3K isoforms were assayed underinitial rate conditions in the presence of 25 mM Hepes (pH 7.4), and2×Km ATP (100-300 μM), 10 μM PIP2, 5% glycerol, 5 mM MgCl2, 50 mM NaCl,0.05% (v/v) Chaps, 1 mM dithiothreitol, 1% (v/v) DMSO at the followingconcentrations for each isoform: PI3K α, β, δ, and γ at 50 picomolar(pM) and PI3Kγ at 2 nanomolar (nM). After an assay reaction time of 30minutes at 25° C., reactions were terminated with a final concentrationof 10 mM EDTA, 10 nM labeled-PIP3, and 35 nM Europium labeled GRP-1detector protein before reading TR-FRET on an Envision plate reader (Ex:340 nm; Em: 615/665 nm; 100 μs delay and 500 μs read window).

Data are normalized based on a positive (1 uM wortmanin) and negative(DMSO) controls PI3K α, β, δ, and γ IC₅₀ values were calculated from thefit of the dose-response curves to a four-parameter equation. IC₅₀ arereported in units of nM. These assays generally produced results within3-fold of the reported mean. The data collected from these assays aresummarized in Table 2 below.

TABLE 2 Summary of IC₅₀ data Compound No. IC₅₀-PIP-α IC₅₀-PIP-βIC₅₀-PIP-δ IC₅₀-PIP-γ   1a >1 uM >1 uM <100 nM >1 uM   2a >1 uM >1 uM<100 nM >1 uM   3a >1 uM >1 uM <100 nM <1 uM and >100 nM   4a >1 uM <1uM and >100 nM <100 nM >1 uM   5a >1 uM >1 uM <100 nM >1 uM   6a >1 uM<1 uM and >100 nM <100 nM <1 uM and >100 nM   7a >1 uM >1 uM <100 nM >1uM   8a >1 uM >1 uM <100 nM >1 uM   9a >1 uM >1 uM <100 nM >1 uM  10a >1uM <1 uM and >100 nM <100 nM <1 uM and >100 nM  11a >1 uM <1 uM and >100nM <100 nM >1 uM  12a >1 uM <1 uM and >100 nM <100 nM <1 uM and >100 nM 13a >1 uM <1 uM and >100 nM <100 nM >1 uM  14a >1 uM >1 uM <1 uMand >100 nM >1 uM  15a <1 uM and >100 nM <100 nM <100 nM <1 uM and >100nM  16a >1 uM <100 nM <100 nM <1 uM and >100 nM  17a <1 uM and >100 nM<1 uM and >100 nM <100 nM <100 nM  18a <100 nM <100 nM <100 nM <100 nM 19a >1 uM >1 uM <100 nM >1 uM  19b >1 uM >1 uM <100 nM >1 uM  20a >1uM >1 uM <100 nM >1 uM  20b >1 uM >1 uM <100 nM >1 uM  23a >1 uM >1 uM<100 nM >1 uM  24a >1 uM >1 uM <100 nM >1 uM  25a <1 uM and >100 nM <1uM and >100 nM <100 nM <100 nM  26a >1 uM >1 uM <1 uM and >100 nM >1 uM 27a >1 uM >1 uM <100 nM <1 uM and >100 nM  28a >1 uM >1 uM <100 nM >1uM  29a >1 uM >1 uM <100 nM >1 uM  30a <1 uM and >100 nM <100 nM <100 nM<1 uM and >100 nM  31a <100 nM <100 nM <100 nM <100 nM  32a <1 uMand >100 nM <1 uM and >100 nM <100 nM <1 uM and >100 nM  33a <100 nM<100 nM <100 nM <100 nM  34a >1 uM <1 uM and >100 nM <100 nM <1 uMand >100 nM  35a <100 nM <100 nM <100 nM <100 nM  36a >1 uM >1 uM <1 uMand >100 nM >1 uM  37a >1 uM <1 uM and >100 nM <100 nM <1 uM and >100 nM 38a <1 uM and >100 nM <100 nM <100 nM >1 uM  39a <1 uM and >100 nM <1uM and >100 nM <100 nM <1 uM and >100 nM  40a <1 uM and >100 nM <1 uMand >100 nM <100 nM <1 uM and >100 nM  41a >1 uM >1 uM <100 nM >1 uM 42a >1 uM >1 uM <100 nM <1 uM and >100 nM  43a >1 uM >1 uM <100 nM <1uM and >100 nM  44a <1 uM and >100 nM <1 uM and >100 nM <100 nM <100 nM 45a >1 uM >1 uM <100 nM >1 uM  46a <1 uM and >100 nM <100 nM <100 nM<100 nM  47a >1 uM <1 uM and >100 nM <100 nM <1 uM and >100 nM  48a >1uM <1 uM and >100 nM <100 nM <1 uM and >100 nM  49a <1 uM and >100 nM<100 nM <100 nM <100 nM  50a <1 uM and >100 nM <100 nM <100 nM <1 uMand >100 nM  51a <1 uM and >100 nM <100 nM <100 nM <100 nM  52a >1 uM >1uM <100 nM >1 uM  53a >1 uM >1 uM <100 nM >1 uM  54a >1 uM <1 uMand >100 nM <100 nM <1 uM and >100 nM  55a >1 uM >1 uM <100 nM >1 uM 56a >1 uM >1 uM <100 nM >1 uM  57a >1 uM >1 uM <100 nM >1 uM  58a >1uM >1 uM <1 uM and >100 nM >1 uM  59a >1 uM >1 uM <1 uM and >100 nM >1uM  60a >1 uM >1 uM <100 nM >1 uM  61a >1 uM >1 uM <100 nM >1 uM  62a >1uM <1 uM and >100 nM <100 nM <1 uM and >100 nM  63a >1 uM >1 uM <100nM >1 uM  64a >1 uM >1 uM <100 nM >1 uM  65a >1 uM >1 uM <100 nM >1 uM 66a >1 uM >1 uM <100 nM >1 uM  67a >1 uM >1 uM <100 nM <1 uM and >100nM  68a >1 uM >1 uM <100 nM >1 uM  69a >1 uM <1 uM and >100 nM <100nM >1 uM  70a >1 uM >1 uM <100 nM >1 uM  71a >1 uM >1 uM <100 nM >1 uM 72a >1 uM >1 uM <100 nM >1 uM  73a >1 uM <1 uM and >100 nM <100 nM >1uM  74a >1 uM >1 uM <100 nM >1 uM  75a <1 uM and >100 nM <100 nM <100 nM<1 uM and >100 nM  76a >1 uM <1 uM and >100 nM <100 nM <1 uM and >100 nM 77a >1 uM >1 uM <100 nM >1 uM  78a >1 uM >1 uM <100 nM <1 uM and >100nM  79a >1 uM <100 nM <100 nM <1 uM and >100 nM  80a <100 nM <100 nM<100 nM <100 nM 81-1a >1 uM >1 uM <100 nM >1 uM 81-2a >1 uM >1 uM <100nM >1 uM  82a >1 uM >1 uM <100 nM >1 uM  83a >1 uM >1 uM <100 nM <1 uMand >100 nM  84a >1 uM >1 uM <100 nM <1 uM and >100 nM  85a >1 uM >1 uM<100 nM >1 uM  86a >1 uM <1 uM and >100 nM <100 nM >1 uM  87a >1 uM >1uM <100 nM >1 uM  88a >1 uM >1 uM <100 nM >1 uM  89a >1 uM <1 uMand >100 nM <100 nM <1 uM and >100 nM  90a >1 uM >1 uM <100 nM >1 uM 91a >1 uM <1 uM and >100 nM <100 nM >1 uM  92a >1 uM >1 uM <100 nM >1uM  93a >1 uM >1 uM <100 nM >1 uM  94a >1 uM >1 uM <100 nM >1 uM  95a >1uM >1 uM <100 nM >1 uM  96a >1 uM >1 uM <100 nM >1 uM  97a >1 uM >1 uM<100 nM >1 uM  98a <1 uM and >100 nM <100 nM <100 nM <1 uM and >100 nM 99a >1 uM >1 uM <100 nM >1 uM 100a >1 uM >1 uM <100 nM >1 uM 101a >1uM >1 uM <100 nM >1 uM 102a >1 uM <1 uM and>100 nM <100 nM <1 uMand >100 nM 103a >1 uM >1 uM <100 nM >1 uM 104a >1 uM <1 uM and >100 nM<100 nM <1 uM and >100 nM 105a >1 uM >1 uM <100 nM >1 uM 106a >1 uM <1uM and >100 nM <100 nM >1 uM 107a >1 uM >1 uM <100 nM >1 uM 108a >1uM >1 uM <100 nM >1 uM 109a >1 uM <1 uM and >100 nM <100 nM >1 uM110a >1 uM >1 uM <100 nM >1 uM 111a >1 uM <1 uM and>100 nM <100 nM <1 uMand >100 nM 112a <1 uM and >100 nM >1 uM <100 nM <1 uM and >100 nM113a >1 uM >1 uM <100 nM >1 uM 114a >1 uM <1 uM and >100 nM <100 nM <1uM and >100 nM 115a >1 uM <1 uM and >100 nM <100 nM >1 uM 116a <1 uMand >100 nM <1 uM and >100 nM <100 nM >1 uM 117a >1 uM >1 uM <100 nM >1uM 118a >1 uM <1 uM and >100 nM <100 nM >1 uM 119a >1 uM <1 uM and >100nM <100 nM >1 uM 120a >1 uM >1 uM <100 nM >1 uM 121a >1 uM <1 uMand >100 nM <100 nM >1 uM 122a >1 uM <1 uM and >100 nM <100 nM >1 uM123a >1 uM <1 uM and >100 nM <100 nM <1 uM and >100 nM 124a >1 uM >1 uM<100 nM >1 uM 125a >1 uM >1 uM <100 nM >1 uM 126a >1 uM >1 uM <100 nM >1uM 127a >1 uM <100 nM <100 nM >1 uM 128a >1 uM >1 uM <100 nM >1 uM129a >1 uM >1 uM <100 nM >1 uM 130a >1 uM >1 uM <100 nM >1 uM 131a >1uM >1 uM <100 nM >1 uM 132a >1 uM >1 uM <100 nM <100 nM 133a >1 uM <1 uMand >100 nM <100 nM <100 nM 134a >1 uM >1 uM <1 uM and >100 nM <1 uMand >100 nM 135a >1 uM <1 uM and >100 nM <100 nM <100 nM 136a >1 uM >1uM <100 nM >1 uM and >100 nM 137a >1 uM >1 uM <1 uM and >100 nM >1 uM138a >1 uM >1 uM <100 nM >1 uM 139b >1 uM <1 uM and >100 nM <100 nM >1uM 140a >1 uM <1 uM and >100 nM <100 nM >1 uM 141a >1 uM <100 nM <100 nM<1 uM and >100 nM 142a >1 uM <100 nM <100 nM <1 uM and >100 nM 143a >1uM <100 nM <100 nM <1 uM and >100 nM 144a >1 uM <1 uM and >100 nM <100nM >1 uM 145a >1 uM >1 uM <100 nM >1 uM 146b >1 uM >1 uM <100 nM >1 uM147a <1 uM and >100 nM <100 nM <100 nM <1 uM and >100 nM 148a >1 uM <1uM and >100 nM <100 nM <1 uM and >100 nM 149a >1 uM <100 nM <100 nM <100nM 150a >1 uM <1 uM and >100 nM <100 nM <100 nM 151a >1 uM <1 uMand >100 nM <100 nM <1 uM and >100 nM 152a >1 uM <1 uM and >100 nM <100nM >1 uM 153a >1 uM <1 uM and >100 nM <100 nM <1 uM and >100 nM 154a <1uM and >100 nM <100 nM <100 nM <100 nM 155a <1 uM and >100 nM >1 nM <100nM <100 nM 156a <1 uM and >100 nM <100 nM <100 nM <1 uM and >100 nM157a >1 uM <100 nM <100 nM <1 uM and >100 nM 158a >1 uM <1 uM and >100nM <100 nM >1 uM 159a >1 uM >1 uM <100 nM >1 uM 160a <1 uM and >100 nM<100 nM <100 nM >1 uM 161a <100 nM <100 nM <100 nM <100 nM 162a >1 uM <1uM and >100 nM <100 nM >1 uM 163a >1 uM >1 uM >1 uM >1 uM 164a >1 uM >1uM <100 nM <1 uM and >100 nM

What is claimed is:
 1. A compound having the structure of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ isunsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, or unsubstituted or substituted alkyl; nis 0, 1, 2, or 3; each R² is independently halo or unsubstituted orsubstituted alkyl; R³ is unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl, unsubstituted or substitutedcycloalkyl, or unsubstituted or substituted heterocycloalkyl; R⁴ ishydrogen, alkyl, or NH₂; R⁵ is alkyl; and R⁶ is hydrogen, or R⁵ togetherwith the carbon to which it is attached and R⁶ together with thenitrogen to which it is attached are taken together to form a, four-,five- or six-membered heterocycle.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is: unsubstitutedaryl; unsubstituted heteroaryl; unsubstituted cycloalkyl; aryl,heteroaryl, or cycloalkyl substituted with 1 or 2 substituentsindependently selected from the group consisting of halo, —OR^(1a),—C(O)OR^(1a), —C(O)R^(1a), NH₂, alkyl, and haloalkyl, wherein R^(1a) isalkyl or haloalkyl; unsubstituted alkyl; or alkyl substituted with OH.3. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is:


4. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each R² is independently halo or unsubstituted alkyl,alkyl substituted with cyano or haloalkyl.
 5. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R³ is:unsubstituted C₆₋₁₂ aryl; or C₆₋₁₂ aryl substituted with 1 or 2substituents independently selected from the group consisting of halo,alkyl, haloalkyl, cyano, —C(O)NR^(3a)R^(3b) and —SO₂NR^(3a)R^(3b),wherein R^(3a) and R^(3b) are independently hydrogen or C₁₋₆ alkyl. 6.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is:


7. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁴ is hydrogen, C₁₋₆ alkyl, or NH₂.
 8. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ isC₁₋₆ alkyl.
 9. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R⁶ is hydrogen.
 10. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁵ together with thecarbon to which it is attached and R⁶ together with the nitrogen towhich it is attached are taken together to form a five- or six-memberedheterocycloalkyl.
 11. The compound of claim 1, wherein the compound isthe (S)-enantiomer.
 12. The compound of claim 1, wherein the compoundhas the structure of formula (IA):

or a pharmaceutically acceptable salt thereof, wherein: R¹ isunsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, or unsubstituted or substituted alkyl; nis 0, 1, 2, or 3; each R² is independently halo or alkyl; R³ isunsubstituted or substituted aryl; and R⁴ is hydrogen or NH₂.
 13. Thecompound of claim 1, wherein the compound has the structure of formula(IB):

or a pharmaceutically acceptable salt thereof, wherein: R¹ isunsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, or unsubstituted or substituted alkyl; nis 0, 1, 2, or 3; each R² is independently halo or unsubstituted orsubstituted alkyl; R⁴ is hydrogen or NH₂; m is 0, 1 or 2; and each R⁷ isindependently halo, —C(O)NR^(3a)R^(3b) and —S(O)₂NR^(3a)R^(3b), whereinR^(3a) and R^(3b) are independently hydrogen or C₁₋₆ alkyl.
 14. Thecompound of claim 1, wherein the compound has the structure of formula(IC):

or a pharmaceutically acceptable salt thereof, wherein: R¹ isunsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, or unsubstituted or substituted alkyl;R^(2a) and R^(2b) are independently hydrogen, halo or unsubstituted orsubstituted alkyl; R⁴ is hydrogen, alkyl, or NH₂; and R^(7a) and R^(7b)are independently hydrogen, halo, —C(O)NR^(3a)R^(3b) and—S(O)₂NR^(3a)R^(3b), wherein R^(3a) and R^(3b) are independentlyhydrogen or C₁₋₆ alkyl.
 15. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of:(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-5,8-difluoroquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-8-fluoroquinazolin-4(3H)-one;(S)-methyl6-((4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)nicotinate;(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5,8-difluoro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8-chloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-8-fluoro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((5-methoxypyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5,8-dichloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5,8-dichloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((5-methoxypyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-8-fluoro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-(pyridazin-3-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((6-aminopyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-(pyrazin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((6-amino-4-(trifluoromethyl)pyridin-3-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((6-amino-4-(trifluoromethyl)pyridin-3-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;2-((S)-1-((6-amino-5-((R)-3-hydroxybut-1-yn-1-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;2-((S)-1-((6-amino-5-((S)-3-hydroxybut-1-yn-1-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;2-((S)-1-((6-amino-5-((R)-3-hydroxybut-1-yn-1-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;2-((S)-1-((6-amino-5-((S)-3-hydroxybut-1-yn-1-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-(cyclopropylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-(cyclopropylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;(S)-5-chloro-2-(1-((2,6-diamino-5-(phenylethynyl)pyrimidin-4-yl)amino)ethyl)-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((4-(trifluoromethoxy)phenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((4-(trifluoromethoxy)phenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-(3-hydroxy-3-methylbut-1-yn-1-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-(3-hydroxy-3-methylbut-1-yn-1-yl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((6-aminopyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((2-aminopyrimidin-5-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((2-aminopyrimidin-5-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((5-aminopyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((5-aminopyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)piperidin-2-yl)-5-chloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-(6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)pyrrolidin-2-yl)-5-chloro-3-phenylquinazolin-4(3H)-one;(S)-3-(2-(1-((6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzamide;(S)-3-(2-(1-((6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)-N-ethylbenzenesulfonamide;(S)-3-(2-(1-((6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-4-oxoquinazolin-3(4H)-yl)benzenesulfonamide;(S)-2-(1-((6-amino-5-(pyrimidin-5-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-(pyrimidin-5-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-(pyridin-3-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-(pyridin-3-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((2-aminobenzo[d]thiazol-6-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((3-fluoro-5-methoxyphenyl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-((5-fluoropyridin-2-yl)ethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((5-((1H-pyrazol-4-yl)ethynyl)-6-aminopyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;(S)-2-(1-((6-amino-5-(pyridin-2-ylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;and(S)-2-(1-((6-amino-5-(phenylethynyl)pyrimidin-4-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one,or a pharmaceutically acceptable salt thereof.
 16. A pharmaceuticalcomposition comprising: a compound of claim 1, or a pharmaceuticallyacceptable salt thereof; and at least one pharmaceutically acceptablevehicle.
 17. A method for treating a human, who has or is suspected ofhaving a disease or condition responsive or believed to be responsive tothe inhibition of PI3Kδ activity, comprising administering to the humana compound of claim 1 or a pharmaceutically acceptable salt thereof. 18.The method of claim 17, wherein the disease or condition is aninflammatory disorder, an autoimmune disease, or a cancer.
 19. Themethod of claim 17, wherein the disease or condition is lymphoma,multiple myeloma, or leukemia.
 20. The method of claim 17, wherein thedisease or condition is acute lymphocytic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocyticlymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferativedisease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM),non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL),mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom'smacroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, diffuse largeB-cell lymphoma (DLBCL), pancreatic cancer, bladder cancer, colorectalcancer, breast cancer, prostate cancer, renal cancer, hepatocellularcancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer,esophageal cancer, head and neck cancer, melanoma, neuroendocrinecancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma,non-small cell lung cancer, small-cell lung cancer, colon cancer,systemic lupus erythematosus (SLE), myestenia gravis, rheumatoidarthritis (RA), acute disseminated encephalomyelitis, idiopathicthrombocytopenic purpura, multiple sclerosis (MS), Sjoegren's syndrome,autoimmune hemolytic anemia, asthma, rheumatoid arthritis, multiplesclerosis, or lupus.